Antibodies that bind polypeptides involved in the process of bone remodeling

ABSTRACT

This invention relates, in part, to unique and newly identified genetic polynucleotides involved in the process of bone remodeling; variants and derivatives of the polynucleotides and corresponding polypeptides; uses of the polynucleotides, polypeptides, variants and derivatives; and methods and compositions for the amelioration of symptoms caused by bone remodeling disorders. Disclosed in particular are, the isolation and identification of polynucleotides, polypeptides, variants and derivatives involved in osteoclast activity, validation of the identified polynucleotides for their potential as therapeutic targets and use of the polynucleotides, polypeptides, variants and derivatives for the amelioration of disease states and research purposes.

RELATED APPLICATIONS

This patent application is a continuation of U.S. Ser. No. 13/152,205filed on Jun. 2, 2011, which is a divisional of U.S. Ser. No.12/279,054, now U.S. Pat. No. 7,989,160, which is a national stagefiling under 35 U.S.C. § 371 of international application No.PCT/CA2007/000210 filed on February 13, 2007, which claimed priority toUnited States provisional application No. 60/772,585 filed on Feb. 13,2006 and United States provisional application No. 60/816,858 filed Jun.28, 2006. The entire contents of each of these priority applications areincorporated herein by reference.

FIELD OF THE INVENTION

This invention relates, in part, to unique and newly identified geneticpolynucleotides involved in the process of bone remodeling; variants andderivatives of the polynucleotides and corresponding polypeptides; usesof the polynucleotides, polypeptides, variants and derivatives; methodsand compositions for the amelioration of symptoms caused by boneremodeling disorders, including but not limited to osteoporosis,osteopenia, osteomalacia, hyperparathyroidism, hypothyroidism,hyperthyroidism, hypogonadism, thyrotoxicosis, systemic mastocytosis,adult hypophosphatasia, hyperadrenocorticism, osteogenesis imperfecta,Paget's disease, Cushing's disease/syndrome, Tumer syndrome, Gaucherdisease, Ehlers-Danlos syndrome, Marfan's syndrome, Menkes' syndrome,Fanconi's syndrome, multiple myeloma, hypercalcemia, hypocalcemia,arthritides, periodontal disease, rickets (including vitamin Ddependent, type I and II, and x-linked hypophosphatemic rickets),fibrogenesis imperfecta ossium, osteosclerotic disorders such aspycnodysostosis and damage caused by macrophage-mediated inflammatoryprocesses.

In particular, this invention relates to polynucleotide expressionprofiles of active osteoclasts, the isolation and identification ofpolynucleotides, polypeptides, variants and derivatives involved inosteoclast activity, validation of the identified polynucleotides fortheir potential as therapeutic targets and use of the polynucleotides,polypeptides, variants and derivatives for the amelioration of diseasestates and research purposes, as well as in diagnosis of disease statesor in the predisposition to develop same.

SEQUENCE LISTING

The present specification makes reference to a Sequence Listing(submitted electronically as a .txt file named “Sequence Listing.txt” onJul. 25, 2012) The .txt file was generated on Jul. 25, 2012 and is 254kb in size. The entire contents of the Sequence Listing are hereinincorporated by reference.

BACKGROUND OF THE INVENTION

Bone is a dynamic connective tissue comprised of functionally distinctcell populations required to support the structural, mechanical andbiochemical integrity of bone and the human body's mineral homeostasis.The principal cell types involved include, osteoblasts responsible forbone formation and maintaining bone mass, and osteoclasts responsiblefor bone resorption. Osteoblasts and osteoclasts function in a dynamicprocess termed bone remodeling. The development and proliferation ofthese cells from their progenitors is governed by networks of growthfactors and cytokines produced in the bone microenvironment as well asby systemic hormones. Bone remodeling is ongoing throughout the lifetimeof the individual and is necessary for the maintenance of healthy bonetissue and mineral homeostasis. The process remains largely inequilibrium and is governed by a complex interplay of systemic hormones,peptides and downstream signalling pathway proteins, local transcriptionfactors, cytokines, growth factors and matrix remodeling genes.

Any interference or imbalance arising in the bone remodeling process canproduce skeletal disease, with the most common skeletal disorderscharacterized by a net decrease in bone mass. A primary cause of thisreduction in bone mass is an increase in osteoclast number and/oractivity. The most common of such disease, and perhaps the best known,is osteoporosis occurring particularly in women after the onset ofmenopause. In fact osteoporosis is the most significant underlying causeof skeletal fractures in late middle-aged and elderly women. Whileestrogen deficiency has been strongly implicated as a factor inpostmenopausal osteoporosis, there is longstanding evidence thatremodeling is a locally controlled process being that it takes place indiscrete packets throughout the skeleton as first described by Frostover forty years ago (Frost H. M. 1964).

Since bone remodeling takes place in discrete packets, locally producedhormones and enzymes may be more important than systemic hormones forthe initiation of bone resorption and the normal remodeling process.Such local control is mediated by osteoblasts and osteoclasts in themicroenvironment in which they operate. For example, osteoclasts attachto the bone matrix and form a separate compartment between themselvesand the bone surface delimited by a sealing zone formed by a ring ofactin surrounding the ruffled border. Multiple small vesicles transportenzymes toward the bone matrix and internalize partially digested bonematrix. The microenvironment within the sealing zone is rich with thepresence of lysosomal enzymes and is highly acidic compared to thenormal physiological pH of the body. The ruffled border membrane alsoexpresses RANK, the receptor for RANKL, and macrophage-colonystimulating factor (M-CSF) receptor, both of which are responsible forosteoclast differentiation, as well as the calcitonin receptor capableof rapidly inactivating the osteoclast (Baron, R. 2003).

In a complex pattern of inhibition and stimulation not yet fullyunderstood, growth hormone, insulin-like growth factor-1, the sexsteroids, thyroid hormone, calciotrophic hormones such as PTH andprostaglandin E2, various cytokines, such as interleukin-1 beta,interleukin-6, and tumour necrosis factor-alpha, and1,25-dihydroxyvitamin D (calcitriol) act co-ordinately in the boneremodeling process (Jilka et al. 1992; Poli et al. 1994; Srivastava etal. 1998; de Vemejoul 1996).

Thus, it stands to reason that the unique local environments created bythese specialized cells is due to the expression of either uniquegenetic sequences not expressed in other tissues and/or splice variantsof polynucleotides and polypeptides expressed in other tissues. Theisolation and identification of polynucleotides, polypeptides and theirvariants and derivatives specific to osteoclast activity will permit aclearer understanding of the remodeling process and offer tissuespecific therapeutic targets for the treatment of disease states relatedto bone remodeling.

Many diseases linked to bone remodeling are poorly understood, generallyuntreatable or treatable only to a limited extent. For example,osteoarthritis is difficult to treat as there is no cure and treatmentfocuses on relieving pain and preventing the affected joint frombecoming deformed. Non-steroidal anti-inflammatory drugs (NSAIDs) aregenerally used to relieve pain.

Another example is osteoporosis where the only current medicationsapproved by the FDA for use in the United States are the anti-resorptiveagents that prevent bone breakdown. Estrogen replacement therapy is oneexample of an anti-resorptive agent. Others include alendronate(Fosamax—a biphosphonate anti-resorptive), risedronate (Actonel—abisphosphonate anti-resorptive), raloxifene (Evista—selective estrogenreceptor modulator (SERM)), calcitonin (Calcimar—a hormone), andparathyroid hormone/teriparatide (Forteo—a synthetic version of thehuman hormone, parathyroid hormone, which helps to regulate calciummetabolism).

Bisphosphonates such as alendronate and risedronate bind permanently tothe surface of bone and interfere with osteoclast activity. This allowsthe osteoblasts to outpace the rate of resorption. The most common sideeffects are nausea, abdominal pain and loose bowel movements. However,alendronate is reported to also cause irritation and inflammation of theesophagus, and in some cases, ulcers of the esophagus. Risedronate ischemically different from alendronate and has less likelihood of causingesophagus irritation. However, certain foods, calcium, iron supplements,vitamins and minerals, or antacids containing calcium, magnesium, oraluminum can reduce the absorption of risedronate, thereby resulting inloss of effectiveness.

The most common side effect of Raloxifen and other SERMS (such asTamoxifen) are hot flashes. However, Raloxifene and other hormonereplacement therapies have been shown to increase the risk of bloodclots, including deep vein thrombosis and pulmonary embolism,cardiovascular disease and cancer.

Calcitonin is not as effective in increasing bone density andstrengthening bone as estrogen and the other anti-resorptive agents.Common side effects of either injected or nasal spray calcitonin arenausea and flushing. Patients can develop nasal irritations, a runnynose, or nosebleeds. Injectable calcitonin can cause local skin rednessat the site of injection, skin rash, and flushing.

A situation demonstrative of the link between several disorders ordisease states involving bone remodeling is that of the use ofetidronate (Didronel) first approved by the FDA to treat Paget'sdisease. Paget's disease is a bone disease characterized by a disorderlyand accelerated remodeling of the bone, leading to bone weakness andpain. Didronel has been used ‘off-label’ and in some studies shown toincrease bone density in postmenopausal women with establishedosteoporosis. It has also been found effective in preventing bone lossin patients requiring long-term steroid medications (such as Prednisoneor Cortisone). However, high dose or continuous use of Didronel cancause another bone disease called osteomalacia. Like osteoporosis,osteomalacia can lead to weak bones with increased risk of fractures.Because of osteomalacia concerns and lack of enough studies yetregarding reduction in the rate of bone fractures, the United States FDAhas not approved Didronel for the treatment of osteoporosis.

Osteoporosis therapy has been largely focused on antiresorptive drugsthat reduce the rate of bone loss but emerging therapies show promise inincreasing bone mineral density instead of merely maintaining it orslowing its deterioration. The osteoporosis early stage pipelineconsists largely of drug candidates in new therapeutic classes, inparticular cathepsin K inhibitors, osteoprotegerin and calcilytics aswell as novel bisphosphonates. Some of these are examples where noveldrugs exploiting genomics programs are being developed based on a deeperunderstanding of bone biology and have the potential to change the faceof treatment of bone disorders in the long term.

There thus remains a need to better understand the bone remodelingprocess and to provide new compositions that are useful for thediagnosis, prognosis, treatment, prevention and evaluation of therapiesfor bone remodeling and associated disorders. A method for analysingpolynucleotide expression patterns has been developed and applied toidentify polynucleotides, polypeptides, variants and derivativesspecifically involved in bone remodeling.

The present invention seeks to meet these and other needs.

The present description refers to a number of documents, the content ofwhich is herein incorporated by reference in their entirety.

SUMMARY OF THE INVENTION

The present invention relates to polynucleotides comprising sequencesinvolved in the process of bone remodeling, the open reading frame ofsuch sequences, substantially identical sequences (e.g., variants (e.g.,allelic variant), non human orthologs), substantially complementarysequences and fragments of any one of the above thereof.

The present invention relates to polypeptide comprising sequencesinvolved in the process of bone remodeling including biologically activeanalogs and biologically active fragments thereof. The present inventionalso relates to compositions that are useful for the diagnosis,prognosis, treatment, prevention and/or evaluation of therapies for boneremodeling and associated disorders.

In addition, the present invention relates to a method for analyzingpolynucleotide expression patterns, and applied in the identification ofpolynucleotides, polypeptides, variants and derivatives specificallyinvolved in bone remodeling.

The present invention relates to polynucleotide expression profiles ofosteoclasts, the isolation and identification of polynucleotides, theircorresponding polypeptides, variants and derivatives involved inosteoclast activity, validation of these identified elements for theirpotential as therapeutic targets and use of said polynucleotides,polypeptides, variants and derivatives for the amelioration of diseasestates.

It is an object of the present invention to provide polynucleotidesand/or related polypeptides that have been isolated and identified. Morespecifically, the invention provides (isolated or substantiallypurified) polynucleotides comprising or consisting of any one of SEQ.ID. NOs:1 to 33, SEQ ID NO.:85 or SEQ ID NO.:86 their coding sequence(open reading frame) substantially identical sequence (e.g., variants,orthologs (e.g., SEQ ID NO.:35)), substantially complementary sequencesand related polypeptides comprising any one of SEQ ID NO.: 48-80 andpolypeptides encoded by SEQ ID NO.:85 or SEQ ID NO.:86 which have beenshown to be upregulated in a highly specific fashion in osteoclasts. Thepresent invention also relates to polypeptide analogs, variants (e.g.,SEQ ID NO.:81) and fragments thereof.

NSEQ refers generally to polynucleotide sequences of the presentinvention and includes for example, SEQ. ID. NOs:1 to 33, SEQ ID NO.:85or SEQ ID NO.:86 whereas PSEQ refers generally to polypeptide sequencesof the present invention and includes, for example, SEQ ID NO.:48 to 82and polypeptides encoded by SEQ ID NO.:85 or SEQ ID NO.:86. Of course itwill be understood that NSEQ also encompasses polynucleotide sequenceswhich are designed or derived from SEQ. ID. NOs:1 to 33 SEQ ID NO.:85 orSEQ ID NO.:86 for example, their coding sequence, complementarysequences. Non-limiting examples of such sequences are disclosed herein(e.g. SEQ ID Nos 42-45).

As used herein the term “NSEQ” refers generally to polynucleotidessequences comprising or consisting of any one of SEQ. ID. NOs:1 to 33,85 or 86 (e.g., an isolated form) or comprising or consisting of afragment of any one of SEQ. ID. NOs:1 to 33, 85 or 86. The term “NSEQ”more particularly refers to a polynucleotide sequence comprising orconsisting of a transcribed portion of any one of SEQ. ID. NOs:1 to 33,85 or 86, which may be, for example, free of untranslated oruntranslatable portion(s) (i.e., a coding portion of any one of SEQ IDNos.: 1 to 33, 85 or 86). The term “NSEQ” additionally refers to asequence substantially identical to any one of the above and moreparticularly substantially identical to polynucleotide sequencecomprising or consisting of a transcribed portion of any one of SEQ. ID.Nos1 to 33, 85 or 86, which may be, for example, free of untranslated oruntranslatable portion(s). The term “NSEQ” additionally refers to apolynucleotide sequence region of any one of SEQ. ID. NOs:1 to 33, 85 or86 which encodes or is able to encode a polypeptide. The term “NSEQ”also refers to a polynucleotide sequence able of encoding any one of thepolypeptides described herein or a polypeptide fragment of any one ofthe above. Finally, the term “NSEQ” also comprise a sequencesubstantially complementary to any one of the above.

The term “inhibitory NSEQ” generally refers to a sequence substantiallycomplementary to any one of SEQ. ID. Nos: 1 to 33, 85 or 86,substantially complementary to a fragment of any one of SEQ. ID. Nos: 1to 33, 85 or 86, substantially complementary to a sequence substantiallyidentical to SEQ. ID. NOs:1 to 33, 85 or 86 and more particularly,substantially complementary to a transcribed portion of any one of SEQ.ID. NOs:1 to 33, 85 or 86 (e.g., which may be free of unstranslated oruntranslatable portion) and which may have attenuating or eveninhibitory action againts the transcription of a mRNA or againstexpression of a polypeptide encoded by a corresponding SEQ ID NOs.:1 to33, 85 or 86. Suitable “inhibitory NSEQ” may have for example andwithout limitation from about 10 to about 30 nucleotides, from about 10to about 25 nucleotides or from about 15 to about 20 nucleotides. Asused herein the term “nucleotide” means deoxyribonucleotide orribonucleotide. In an exemplary embodiment, the use of nucleotideanalogues is also encompassed in the present invention.

The present invention relates in one aspect thereof to an isolatedpolynucleotide sequence having at least from about 80% to about 100%(e.g., 80%, 90%, 95%, etc.) sequence identity to a polynucleotidesequence selected from the group consisting of polynucleotidescomprising (a) any one of a SEQ. ID. NOs:1 to 33 or SEQ ID NO.:85 or SEQID NO.:86; (b) an open reading frame of (a); (c) a full complement of(a) or (b), and; (d) a fragment of any one of (a) to (c).

As used herein the term “unstranscribable region” may include forexample, a promoter region (or portion thereof), silencer region,enhancer region etc. of a polynucleotide sequence.

As used herein the term “unstranslatable region” may include forexample, an initiator portion of a polynucleotide sequence (upstream ofan initiator codon, e.g., AUG), intronic regions, stop codon and/orregion downstream of a stop codon (including polyA tail, etc.).

Complements of the isolated polynucleotide sequence encompassed by thepresent invention may be those, for example, which hybridize under highstringency conditions to any of the nucleotide sequences in (a), or (b).The high stringency conditions may comprise, for example, ahybridization reaction at 65° C. in 5×SSC, 5×Denhardt's solution, 1%SDS, and 100 μg/ml denatured salmon sperm DNA.

In accordance with the present invention, the polynucleotide sequencemay be used, for example, in the treatment of diseases or disordersinvolving bone remodeling.

Fragments of polynucleotides may be used, for example, as probes fordetermining the presence of the isolated polynucleotide (or itscomplement or fragments thereof) in a sample, cell, tissue, etc. forexperimental purposes or for the purpose of diagnostic of a diseases ordisorders involving bone remodeling.

The present invention also relates to a combination comprising aplurality of polynucleotides (substantially purified and/or isolated).The polynucleotides may be co-expressed with one or more genes known tobe involved in bone remodeling. Furthermore, the plurality ofpolynucleotides may be selected, for example, from the group consistingof a polynucleotide comprising (a) any one of SEQ. ID. NOs:1 to 33, SEQID NO.:85 or SEQ ID NO.:86; (b) an open reading frame (a); (c) apolynucleotide sequence comprising or consisting of a transcribedportion of any one of SEQ. ID. NOs:1 to 33, 85 or 86, which may be, forexample, free of untranslated or untranslatable portion(s) (d) acomplementary sequence of any one of (a) to (c); (e) a sequence thathybridizes under high stringency conditions to any one of the nucleotidesequences of (a) to (d) and; (f) fragments of any one of (a) to (e).

The present invention further relates to a polynucleotide encoding anyone of the polypeptides described herein. In accordance with the presentinvention, the polynucleotide (RNA, DNA, etc.) may encode a polypeptidewhich may be selected from the group consisting of any one of SEQ IDNO.:48 to 80, polypeptides encoded by SEQ ID NO.:85 or 86, analogs orfragments thereof (e.g., biologically active fragments, immunologicallyactive fragments, etc.).

The present invention also relates to an isolated nucleic acid moleculecomprising the polynucleotides of the present invention, operativelylinked to a nucleotide sequence encoding a heterologous polypeptidethereby encoding a fusion polypeptide.

The invention further relates to a polypeptide encoded by apolynucleotide of SEQ. ID. NOs:1 to 33, SEQ ID NO.:85 or SEQ ID NO.:86or more particularly from the open reading frame of any one of SEQ. ID.NOs:1 to 33, SEQ ID NO.:85 or SEQ ID NO.:86, or a portion thereof. Theinvention also comprise the product of a gene that is co-expressed withone or more genes known to be involved in bone remodeling.

Isolated naturally occurring allelic variant are also encompassed by thepresent invention as well as synthetic variants (e.g., made byrecombinant DNA technology or by chemical synthesis, etc.) such asbiologically active variant which may comprise one or more amino acidsubstitutions (compared to a naturally occurring polypeptide), such asconservative or non conservative amino acid substitution.

The present invention, further provides a vector (mammalian, bacterial,viral, etc.) comprising the polynucleotides described herein orfragments thereof, such as an expression vector. The vector may furthercomprise a nucleic acid sequence which may help in the regulation ofexpression of the polynucleotide and/or a nucleotide sequence encoding atag (e.g., affinity tag; HA, GST, His etc.).

In accordance with the present invention, an expression vector maycomprise, for example, the following operatively linked elements:

-   -   a) a transcription promoter;    -   b) a polynucleotide segment (which may comprise an open reading        frame of any one of SEQ ID NOs.:1-33, 85 or 86); and    -   c) a transcription terminator.

The invention also relates to an expression vector comprising apolynucleotide described herein, a host cell transformed with theexpression vector and a method for producing a polypeptide of thepresent invention.

The invention further relates to a vector comprising a polynucleotide orpolynucleotide fragment. Vectors which may comprise a sequencesubstantially complementary to the polynucleotides of the presentinvention (e.g., siRNA, shRNA) are thus encompassed by the presentinvention. The vector may comprise sequences enabling transcription ofthe polynucleotide or polynucleotide fragment.

More particularly, the present invention therefore provides a cell whichmay be genetically engineered to contain and/or to express thepolynucleotide (including complements and fragments) and/or polypeptidesof the present invention. The cell may be, for example, a mammaliancell, an insect cell, a bacteria cell, etc.

The present invention, therefore provides a host cell which may comprisea vector as described herein. The cell may be, for example, a mammaliancell, an insect cell, a bacteria, etc. The cell may be able to expressor expresses a polypeptide encoded by the polynucleotide describedherein.

Methods of producing the polypeptides of the present inventionencompassed herewith includes for example, culturing the cell inconditions allowing the transcription of a gene or expression of thepolypeptide. The polypeptide may be recovered, for example, from celllysate or from the cell supernatant.

The invention relates to the use of at least one polynucleotidecomprising any one of SEQ. ID. NOs:1 to 33, SEQ ID NO.:85 or SEQ IDNO.:86 their coding sequence, substantially identical sequences,substantially complementary sequences or fragments thereof on an array.The array may be used in a method for diagnosing a bone remodelingdisease or disorder by hybridizing the array with a patient sample underconditions to allow complex formation, detecting complex formation, andcomparing the amount of complex formation in the patient sample to thatof standards for normal and diseased tissues wherein the complexformation in the patient sample indicates the presence of a boneremodeling disease or disorder. Of course, the use of a polynucleotideof the present invention in a diagnosis method is not dependentexclusively by way of a specific assay. The sequence or sequences may beused in conventionally used diagnosis methods known in the art.

The present invention also relates to a method of ameliorating boneremodeling disease or disorder symptoms, or for inhibiting or delayingbone disease or disorder, the method may comprise: contacting a compoundcapable of specifically inhibiting activity or expression of apolynucleotide sequence described herein or a polypeptide describedherein, in osteoclasts so that symptoms of the bone remodeling diseaseor disorder may be ameliorated, or the disease or disorder may beprevented, delayed or lowered.

The present invention further relates to a method for ameliorating boneremodeling disease or disorder symptoms, or for inhibiting or delayingbone disease or disorder, the method may comprise: contacting a compoundcapable of specifically promoting activity or expression of apolynucleotide sequence described herein or a polypeptide describedherein, in osteoclasts so that symptoms of the bone remodeling diseaseor disorder may be ameliorated, or the disease or disorder may beprevented, delayed or lowered.

The present invention also relates to a method of treating a conditionin a mammal characterized by a deficiency in, or need for, bone growthor replacement and/or an undesirable level of bone resorption, whichmethod may comprise administering to a mammalian subject in need of suchtreatment an effective amount of a suitable compound described herein.

The present invention further relates to a method of using apolynucleotide sequence described herein, a polypeptide described hereinon an array and for the use of the array in a method for diagnosing abone remodeling disease or disorder by hybridizing the array with apatient sample under conditions to allow complex formation, detectingcomplex formation, and comparing the amount of complex formation in thepatient sample to that of standards for normal and diseased tissueswherein the complex formation in the patient sample may indicate thepresence of a bone remodeling disease or disorder.

In accordance with the present invention, the polynucleotide sequencedescribed herein may be used for somatic cell gene therapy or for stemcell gene therapy.

The invention also relates to a pharmaceutical composition comprising apolynucleotide described herein or a polypeptide encoded by the selectedpolynucleotide or portion thereof and a suitable pharmaceutical carrier.

Additionally, the invention relates to products, compositions, processesand methods that comprises a polynucleotide described herein, apolypeptide encoded by the polynucleotides, a portion thereof, theirvariants or derivatives, for research, biological, clinical andtherapeutic purposes.

The NSEQs and PSEQs may be used in diagnosis, prognosis, treatment,prevention, and selection and evaluation of therapies for diseases anddisorders involving bone remodeling including, but not limited to,osteoporosis, osteopenia, osteomalacia, hyperparathyroidism,hyperthyroidism, hyperthyroidism, hypogonadism, thyrotoxicosis, systemicmastocytosis, adult hypophosphatasia, hyperadrenocorticism, osteogenesisimperfecta, Paget's disease, Cushing's disease/syndrome, Tumer syndrome,Gaucher disease, Ehlers-Danlos syndrome, Marfan's syndrome, Menkes'syndrome, Fanconi's syndrome, multiple myeloma, hypercalcemia,hypocalcemia, arthritides, periodontal disease, rickets (includingvitamin D dependent, type I and II, and x-linked hypophosphatemicrickets), fibrogenesis imperfecta ossium, osteosclerotic disorders suchas pycnodysostosis and damage caused by macrophage-mediated inflammatoryprocesses.

Use of NSEQ as a Screening Tool

The polynucleotides obtained by the present invention may be used todetect and isolate expression products, for example, mRNA, complementaryDNAs (cDNAs) and proteins derived from or homologous to the NSEQs. Inone embodiment, the expression of mRNAs homologous to the NSEQs of thepresent invention may be detected, for example, by hybridizationanalysis, reverse transcription and in vitro nucleic acid amplificationmethods. Such procedures permit detection of mRNAs in a variety oftissue types or at different stages of development. The subject nucleicacids which are expressed in a tissue-specific or adevelopmental-stage-specific manner are useful as tissue-specificmarkers or for defining the developmental stage of a sample of cells ortissues that may define a particular disease state. One of skill in theart may readily adapt the NSEQs for these purposes.

Those skilled in the art will also recognize that the NSEQs, and itsexpression products such as cDNA nucleic acids and genomic DNA may beused to prepare short oligonucleotides sequences. For example,oligonucleotides having ten to twelve nucleotides or more may beprepared which hybridize specifically to the present NSEQs and cDNAs andallow detection, identification and isolation of unique nucleicsequences by hybridization. Sequences of for example, at least 15-20nucleotides may be used and selected from regions that lack homology toother known sequences. Sequences of 20 or more nucleotides that lacksuch homology show an increased specificity toward the target sequence.Useful hybridization conditions for probes and primers are readilydeterminable by those of skill in the art. Stringent hybridizationconditions encompassed herewith are those that may allow hybridizationof nucleic acids that are greater than 90% homologous but which mayprevent hybridization of nucleic acids that are less than 70%homologous. The specificity of a probe may be determined by whether itis made from a unique region, a regulatory region, or from a conservedmotif. Both probe specificity and the stringency of diagnostichybridization or amplification (maximal, high, intermediate, or low)reactions may be determined whether the probe identifies exactlycomplementary sequences, allelic variants, or related sequences. Probesdesigned to detect related sequences may have at least 50% sequenceidentity to any of the selected polynucleotides.

It is to be understood herein that the NSEQs (substantially identicalsequences and fragments thereof) may hybridize to a substantiallycomplementary sequence found in a test sample. Additionally, a sequencesubstantially complementary to NSEQ may bind a NSEQ found in a testsample.

Furthermore, a probe may be labelled by any procedure known in the art,for example by incorporation of nucleotides linked to a “reportermolecule”. A “reporter molecule”, as used herein, may be a molecule thatprovides an analytically identifiable signal allowing detection of ahybridized probe. Detection may be either qualitative or quantitative.Commonly used reporter molecules include fluorophores, enzymes, biotin,chemiluminescent molecules, bioluminescent molecules, digoxigenin,avidin, streptavidin or radioisotopes. Commonly used enzymes includehorseradish peroxidase, alkaline phosphatase, glucose oxidase andβ-galactosidase, among others. Enzymes may be conjugated to avidin orstreptavidin for use with a biotinylated probe. Similarly, probes may beconjugated to avidin or streptavidin for use with a biotinylated enzyme.Incorporation of a reporter molecule into a DNA probe may be by anymethod known to the skilled artisan, for example by nick translation,primer extension, random oligo priming, by 3′ or 5′ end labeling or byother means. In addition, hybridization probes include the cloning ofnucleic acid sequences into vectors for the production of mRNA probes.Such vectors are known in the art, are commercially available, and maybe used to synthesize RNA probes in vitro. The labelled polynucleotidesequences may be used in Southern or northern analysis, dot blot, orother membrane-based technologies; in PCR technologies; and in microarrays utilizing samples from subjects to detect altered expression.Oligonucleotides useful as probes for screening of samples byhybridization assays or as primers for amplification may be packagedinto kits. Such kits may contain the probes or primers in a pre-measuredor predetermined amount, as well as other suitably packaged reagents andmaterials needed for the particular hybridization or amplificationprotocol. In another embodiment, the invention entails a substantiallypurified polypeptide encoded by the polynucleotides of NSEQs,polypeptide analogs or polypeptide fragments thereof. The polypeptideswhether in a premature, mature or fused form, may be isolated from lysedcells, or from the culture medium, and purified to the extent needed forthe intended use. One of skill in the art may readily purify theseproteins, polypeptides and peptides by any available procedure. Forexample, purification may be accomplished by salt fractionation, sizeexclusion chromatography, ion exchange chromatography, reverse phasechromatography, affinity chromatography and the like.

Use of NSEQ for Development of an Expression System

In order to express a biologically active polypeptide, NSEQ, orderivatives thereof, may be inserted into an expression vector, i.e., avector that contains the elements for transcriptional and translationalcontrol of the inserted coding sequence in a particular host. Theseelements may include regulatory sequences, such as enhancers,constitutive and inducible promoters, and 5′ and 3′ un-translatedregions. Methods that are well known to those skilled in the art may beused to construct such expression vectors. These methods include invitro recombinant DNA techniques, synthetic techniques, and in vivogenetic recombination.

A variety of expression vector/host cell systems known to those of skillin the art may be utilized to express NSEQ. These include, but are notlimited to, microorganisms such as bacteria transformed with recombinantbacteriophage, plasmid, or cosmid DNA expression vectors; yeasttransformed with yeast expression vectors; insect cell systems infectedwith baculovirus vectors; plant cell systems transformed with viral orbacterial expression vectors; or animal cell systems. For long-termproduction of recombinant proteins in mammalian systems, stableexpression in cell lines may be effected. For example, NSEQ may betransformed into cell lines using expression vectors that may containviral origins of replication and/or endogenous expression elements and aselectable or visible marker gene on the same or on a separate vector.The invention is not to be limited by the vector or host cell employed.

In general, host cells that contain NSEQ and that express a polypeptideencoded by the NSEQ, or a portion thereof, may be identified by avariety of procedures known to those of skill in the art. Theseprocedures include, but are not limited to, DNA-DNA or DNA-RNAhybridizations, PCR amplification, and protein bioassay or immunoassaytechniques that include membrane, solution, or chip based technologiesfor the detection and/or quantification of nucleic acid or amino acidsequences. Immunological methods for detecting and measuring theexpression of polypeptides using either specific polyclonal ormonoclonal antibodies are known in the art. Examples of such techniquesinclude enzyme-linked immunosorbent assays (ELISAs), radioimmunoassays(RIAs), and fluorescence activated cell sorting (FACS). Those of skillin the art may readily adapt these methodologies to the presentinvention.

The present invention additionally relates to a bioassay for evaluatingcompounds as potential antagonists of the polypeptide described herein,the bioassay may comprise:

-   -   a) culturing test cells in culture medium containing increasing        concentrations of at least one compound whose ability to inhibit        the action of a polypeptide described herein is sought to be        determined, wherein the test cells may contain a polynucleotide        sequence described herein (for example, in a form having        improved trans-activation transcription activity, relative to        wild-type polynucleotide, and comprising a response element        operatively linked to a reporter gene); and thereafter    -   b) monitoring in the cells the level of expression of the        product of the reporter gene as a function of the concentration        of the potential antagonist compound in the culture medium,        thereby indicating the ability of the potential antagonist        compound to inhibit activation of the polypeptide encoded by,        the polynucleotide sequence described herein.

The present invention further relates to a bioassay for evaluatingcompounds as potential agonists for a polypeptide encoded by thepolynucleotide sequence described herein, the bioassay may comprise:

-   -   a) culturing test cells in culture medium containing increasing        concentrations of at least one compound whose ability to promote        the action of the polypeptide encoded by the polynucleotide        sequence described herein is sought to be determined, wherein        the test cells may contain a polynucleotide sequence described        herein (for example, in a form having improved trans-activation        transcription activity, relative to wild-type polynucleotide,        and comprising a response element operatively linked to a        reporter gene); and thereafter    -   b) monitoring in the cells the level of expression of the        product of the reporter gene as a function of the concentration        of the potential agonist compound in the culture medium, thereby        indicating the ability of the potential agonist compound to        promote activation of a polypeptide encoded by the        polynucleotide sequence described herein.

Host cells transformed with NSEQ may be cultured under conditions forthe expression and recovery of the polypeptide from cell culture. Thepolypeptide produced by a transgenic cell may be secreted or retainedintracellularly depending on the sequence and/or the vector used. Aswill be understood by those of skill in the art, expression vectorscontaining NSEQ may be designed to contain signal sequences that directsecretion of the polypeptide through a prokaryotic or eukaryotic cellmembrane. Due to the inherent degeneracy of the genetic code, other DNAsequences that encode substantially the same or a functionallyequivalent amino acid sequence may be produced and used to express thepolypeptide encoded by NSEQ. The nucleotide sequences of the presentinvention may be engineered using methods generally known in the art inorder to alter the nucleotide sequences for a variety of purposesincluding, but not limited to, modification of the cloning, processing,and/or expression of the gene product. DNA shuffling by randomfragmentation and PCR reassembly of gene fragments and syntheticoligonucleotides may be used to engineer the nucleotide sequences. Forexample, oligonucleotide-mediated site-directed mutagenesis may be usedto introduce mutations that create new restriction sites, alterglycosylation patterns, change codon preference, produce splicevariants, and so forth.

In addition, a host cell strain may be chosen for its ability tomodulate expression of the inserted sequences or to process theexpressed polypeptide in the desired fashion. Such modifications of thepolypeptide include, but are not limited to, acetylation, carboxylation,glycosylation, phosphorylation, lipidation, and acylation.Post-translational processing, which cleaves a “prepro” form of thepolypeptide, may also be used to specify protein targeting, folding,and/or activity. Different host cells that have specific cellularmachinery and characteristic mechanisms for post-translationalactivities (e.g., CHO, HeLa, MDCK, HEK293, and W138) are availablecommercially and from the American Type Culture Collection (ATCC) andmay be chosen to ensure the correct modification and processing of theexpressed polypeptide.

Those of skill in the art will readily appreciate that natural,modified, or recombinant nucleic acid sequences may be ligated to aheterologous sequence resulting in translation of a fusion polypeptidecontaining heterologous polypeptide moieties in any of theaforementioned host systems. Such heterologous polypeptide moieties mayfacilitate purification of fusion polypeptides using commerciallyavailable affinity matrices. Such moieties include, but are not limitedto, glutathione S-transferase (GST), maltose binding protein,thioredoxin, calmodulin binding peptide, 6-His (His), FLAG, c-myc,hemaglutinin (HA), and monoclonal antibody epitopes.

In yet a further aspect, the present invention relates to an isolatedpolynucleotide which may comprise a nucleotide sequence encoding afusion protein, the fusion protein may comprise a fusion partner fusedto a peptide fragment of a protein encoded by, or a naturally occurringallelic variant polypeptide encoded by, the polynucleotide sequencedescribed herein.

Those of skill in the art will also readily recognize that the nucleicacid and polypeptide sequences may be synthesized, in whole or in part,using chemical or enzymatic methods well known in the art. For example,peptide synthesis may be performed using various solid-phase techniquesand machines such as the ABI 431A Peptide synthesizer (PE Biosystems)may be used to automate synthesis. If desired, the amino acid sequencemay be altered during synthesis and/or combined with sequences fromother proteins to produce a variant protein.

Use of NSEQ as a Diagnostic Screening Tool

The skilled artisan will readily recognize that NSEQ may be used fordiagnostic purposes to determine the absence, presence, or alteredexpression (i.e. increased or decreased compared to normal) of the gene.The polynucleotides may be at least 10 nucleotides long or at least 12nucleotides long, or at least 15 nucleotides long up to any desiredlength and may comprise complementary RNA and DNA molecules, branchednucleic acids, and/or peptide nucleic acids (PNAs). In one alternative,the polynucleotides may be used to detect and quantify gene expressionin samples in which expression of NSEQ is correlated with disease. Inanother alternative, NSEQ may be used to detect genetic polymorphismsassociated with a disease. These polymorphisms may be detected in thetranscript cDNA.

The invention provides for the use of at least one polynucleotidecomprising NSEQ (e.g., an open reading frame of NSEQ, a substantiallycomplementary sequence, a substantially identical sequence, andfragments thereof) on an array and for the use of that array in a methodfor diagnosing a bone remodeling disease or disorder by hybridizing thearray with a patient sample under conditions to allow complex formation,detecting complex formation, and comparing the amount of complexformation in the patient sample to that of standards for normal anddiseased tissues wherein the complex formation in the patient sampleindicates the presence of a bone remodeling disease or disorder.

In another embodiment, the present invention provides one or morecompartmentalized kits for detection of bone resorption disease states.A first kit may have a receptacle containing at least one isolatedprobe. Such a probe may be a nucleic acid fragment which ispresent/absent in the genomic DNA of normal cells but which isabsent/present in the genomic DNA of affected cells. Such a probe may bespecific for a DNA site that is normally active/inactive but which maybe inactive/active in certain cell types. Similarly, such a probe may bespecific for a DNA site that may be abnormally expressed in certain celltypes. Finally, such a probe may identify a specific DNA mutation. Byspecific for a DNA site is meant that the probe may be capable ofhybridizing to the DNA sequence which is mutated, or may be capable ofhybridizing to DNA sequences adjacent to the mutated DNA sequences. Theprobes provided in the present kits may have a covalently attachedreporter molecule. Probes and reporter molecules may be readily preparedas described above by those of skill in the art.

Use of NSEQ as a Therapeutic

One of skill in the art will readily appreciate that the expressionsystems and assays discussed above may also be used to evaluate theefficacy of a particular therapeutic treatment regimen, in animalstudies, in clinical trials, or to monitor the treatment of anindividual subject. Once the presence of disease is established and atreatment protocol is initiated, hybridization or amplification assaysmay be repeated on a regular basis to determine if the level ofexpression in the patient begins to approximate the level observed in ahealthy subject. The results obtained from successive assays may be usedto show the efficacy of treatment over a period ranging from severaldays to many years.

In yet another aspect of the invention, an NSEQ, a portion thereof, orits complement, may be used therapeutically for the purpose ofexpressing mRNA and polypeptide, or conversely to block transcription ortranslation of the mRNA. Expression vectors may be constructed usingelements from retroviruses, adenoviruses, herpes or vaccinia viruses, orbacterial plasmids, and the like. These vectors may be used for deliveryof nucleotide sequences to a particular target organ, tissue, or cellpopulation. Methods well known to those skilled in the art may be usedto construct vectors to express nucleic acid sequences or theircomplements.

Alternatively, NSEQ, a portion thereof, or its complement, may be usedfor somatic cell or stem cell gene therapy. Vectors may be introduced invivo, in vitro, and ex vivo. For ex vivo therapy, vectors are introducedinto stem cells taken from the subject, and the resulting transgeniccells are clonally propagated for autologous transplant back into thatsame subject. Delivery of NSEQ by transfection, liposome injections, orpolycationic amino polymers may be achieved using methods that are wellknown in the art. Additionally, endogenous NSEQ expression may beinactivated using homologous recombination methods that insert aninactive gene sequence into the coding region or other targeted regionof NSEQ.

Depending on the specific goal to be achieved, vectors containing NSEQmay be introduced into a cell or tissue to express a missing polypeptideor to replace a non-functional polypeptide. Of course, when one wishesto express PSEQ in a cell or tissue, one may use a NSEQ able to encodesuch PSEQ for that purpose or may directly administer PSEQ to that cellor tissue.

On the other hand, when one wishes to attenuate or inhibit theexpression of PSEQ, one may use a NSEQ (e.g., an inhibitory NSEQ) whichis substantially complementary to at least a portion of a NSEQ able toencode such PSEQ.

The expression of an inhibitory NSEQ may be done by cloning theinhibitory NSEQ into a vector and introducing the vector into a cell todown-regulate the expression of a polypeptide encoded by the targetNSEQ.

Vectors containing NSEQ (e.g., including inhibitory NSEQ) may betransformed into a cell or tissue to express a missing polypeptide or toreplace a non-functional polypeptide. Similarly a vector constructed toexpress the complement of NSEQ may be transformed into a cell todown-regulate the over-expression of a polypeptide encoded by thepolynucleotides of NSEQ, or a portion thereof. Complementary oranti-sense sequences may consist of an oligonucleotide derived from thetranscription initiation site; nucleotides between about positions −10and +10 from the ATG are preferred. Similarly, inhibition may beachieved using triple helix base-pairing methodology. Triple helixpairing is useful because it causes inhibition of the ability of thedouble helix to open sufficiently for the binding of polymerases,transcription factors, or regulatory molecules. Recent therapeuticadvances using triplex DNA have been described in the literature. (See,e.g., Gee et al. 1994)

Ribozymes, enzymatic RNA molecules, may also be used to catalyze thecleavage of mRNA and decrease the levels of particular mRNAs, such asthose comprising the polynucleotide sequences of the invention.Ribozymes may cleave mRNA at specific cleavage sites. Alternatively,ribozymes may cleave mRNAs at locations dictated by flanking regionsthat form complementary base pairs with the target mRNA. Theconstruction and production of ribozymes is well known in the art.

RNA molecules may be modified to increase intracellular stability andhalf-life. Possible modifications include, but are not limited to, theaddition of flanking sequences at the 5′ and/or 3′ ends of the molecule,or the use of phosphorothioate or 2′ O-methyl rather than phosphodiesterlinkages within the backbone of the molecule. Alternatively,nontraditional bases such as inosine, queosine, and wybutosine, as wellas acetyl-, methyl-, thio-, and similarly modified forms of adenine,cytidine, guanine, thymine, and uridine which are not as easilyrecognized by endogenous endonucleases, may be included.

In addition to the active ingredients, a pharmaceutical composition maycontain pharmaceutically acceptable carriers comprising excipients andauxiliaries that facilitate processing of the active compounds intopreparations that may be used pharmaceutically.

For any compound, the therapeutically effective dose may be estimatedinitially either in cell culture assays or in animal models such asmice, rats, rabbits, dogs, or pigs. An animal model may also be used todetermine the concentration range and route of administration. Suchinformation may then be used to determine useful doses and routes foradministration in humans. These techniques are well known to one skilledin the art and a therapeutically effective dose refers to that amount ofactive ingredient that ameliorates the symptoms or condition.Therapeutic efficacy and toxicity may be determined by standardpharmaceutical procedures in cell cultures or with experimental animals,such as by calculating and contrasting the ED₅₀ (the dosetherapeutically effective in 50% of the population) and LD₅₀ (the doselethal to 50% of the population) statistics. Any of the therapeuticcompositions described above may be applied to any subject in need ofsuch therapy, including, but not limited to, mammals such as dogs, cats,cows, horses, rabbits, monkeys, and most preferably, humans.

The pharmaceutical compositions utilized in this invention may beadministered by any number of routes including, but not limited to,oral, intravenous, intramuscular, intra-arterial, intramedullary,intrathecal, intraventricular, transdermal, subcutaneous,intraperitoneal, intranasal, enteral, topical, sublingual, or rectalmeans.

The term “Treatment” for purposes of this disclosure refers to boththerapeutic treatment and prophylactic or preventative measures, whereinthe object is to prevent or slow down (lessen) the targeted pathologiccondition or disorder. Those in need of treatment include those alreadywith the disorder as well as those prone to have the disorder or thosein whom the disorder is to be prevented.

Use of NSEQ in General Research

The invention finally provides products, compositions, processes andmethods that utilize an NSEQ, their open reading frame, or a polypeptideencoded by the polynucleotides of NSEQ or their open reading frame, or aportion thereof, their variants, analogs, derivatives and fragments forresearch, biological, clinical and therapeutic purposes. For example, toidentify splice variants, mutations, and polymorphisms

NSEQ may be extended utilizing a partial nucleotide sequence andemploying various PCR-based methods known in the art to detect upstreamsequences such as promoters and other regulatory elements. Additionally,one may use an XL-PCR kit (PE Biosystems, Foster City Calif.), nestedprimers, and commercially available cDNA libraries (Life Technologies,Rockville Md.) or genomic libraries (Clontech, Palo Alto Calif.) toextend the sequence.

The polynucleotides may also be used as targets in a micro-array. Themicro-array may be used to monitor the expression patterns of largenumbers of genes simultaneously and to identify splice variants,mutations, and polymorphisms. Information derived from analyses of theexpression patterns may be used to determine gene function, tounderstand the genetic basis of a disease, to diagnose a disease, and todevelop and monitor the activities of therapeutic agents used to treat adisease. Microarrays may also be used to detect genetic diversity,single nucleotide polymorphisms which may characterize a particularpopulation, at the genomic level.

In yet another embodiment, polynucleotides may be used to generatehybridization probes useful in mapping the naturally occurring genomicsequence. Fluorescent in situ hybridization (FISH) may be correlatedwith other physical chromosome mapping techniques and genetic map data.

The present invention more particularly relates in one aspect thereof toa method of representatively identifying an endogeneously differentiallyexpressed sequence involved in osteoclast differentiation. The sequencemay be, for example, differentially expressed in a differentiatedosteoclast cell compared to an undifferentiated osteoclast precursorcell.

The method of the present invention may comprise;

-   -   a) separately providing total messenger RNA from (mature or        intermediately) differentiated human osteoclast cell and        undifferentiated human osteoclast precursor cell, the total        messenger RNA may comprise, for example, at least one        endogeneously differentially expressed sequence,    -   b) generating single-stranded cDNA from each messenger RNA of        differentiated human osteoclast cell and (e.g., randomly)        tagging the 3′-end of the single-stranded cDNA with a RNA        polymerase promoter sequence and a first sequence tag;    -   c) generating single-stranded cDNA from each messenger RNA of        undifferentiated human osteoclast precursor cell and (e.g.,        randomly) tagging the 3′-end of the single-stranded cDNA with a        RNA polymerase promoter sequence and a second sequence tag;    -   d) separately generating partially or completely double-stranded        5′-tagged-DNA from each of b) and c), the double-stranded        5′-tagged-DNA may thus comprise in a 5′ to 3′ direction, a        double-stranded RNA polymerase promoter, a first or second        sequence tag and an endogenously expressed sequence,    -   e) separately linearly amplifying a first and second tagged        sense RNA from each of d) with a RNA polymerase enzyme (which        may be selected based on the promoter used for tagging),    -   f) generating single-stranded complementary first or second        tagged DNA from one of e),    -   g) hybridizing the single-stranded complementary first or second        tagged DNA of f) with the other linearly amplified sense RNA of        e),    -   h) recovering unhybridized RNA with the help of the first or        second sequence tag (for example by PCR or hybridization), and;    -   i) identifying (determining) the nucleotide sequence of        unhybridized RNA.

Steps b) and/or c), may comprise generating a single copy of asingle-stranded cDNA.

The method may further comprise the step of comparatively determiningthe presence of the identified endogeneously and differentiallyexpressed sequence in a differentiated osteoclast cell relative to anundifferentiated osteoclast precursor cell.

A sequence which is substantially absent (e.g., totally absent orpresent in very low quantity) from one of differentiated osteoclast cellor an undifferentiated osteoclast precursor cell and present in theother of differentiated osteoclast cell or an undifferentiatedosteoclast precursor cell may therefore be selected.

The sequence thus selected may be a positive regulator of osteoclastdifferentiation and therefore may represent an attractive target whichmay advantageously be used to promote bone resorption or alternativelysuch target may be inhibited to lower or prevent bone resorption.

Alternatively, the sequence selected using the above method may be anegative regulator of osteoclast differentiation and may thereforerepresent an attractive target which may advantageously be induced(e.g., at the level of transcription, translation, activity etc.) orprovided to a cell to lower or prevent bone resorption. Also suchnegative regulator may, upon its inhibition, serve as a target topromote bone resorption.

In accordance with the present invention, the sequence may be furtherselected based on a reduced or substantially absent expression in othernormal tissue, therefore representing a candidate sequence specificallyinvolved in osteoclast differentiation and bone remodeling.

The method may also further comprise a step of determining the completesequence of the nucleotide sequence and may also comprise determiningthe coding sequence of the nucleotide sequence.

The present invention also relates in a further aspect, to the isolatedendogeneously and differentially expressed sequence (polynucleotide andpolypeptide) identified by the method of the present invention.

More particularly, the present invention encompasses a polynucleotidewhich may comprise the identified polynucleotide sequence, apolynucleotide which may comprise the open reading frame of theidentified polynucleotide sequence, a polynucleotide which may comprisea nucleotide sequence substantially identical to the polynucleotideidentified by the method of the present invention, a polynucleotidewhich may comprise a nucleotide sequence substantially complementary tothe polynucleotide identified by the method of the present invention,fragments and splice variant thereof, provided that the sequence doesnot consist in or comprise SEQ ID NO.:34.

In accordance with the present invention, the isolated endogeneously anddifferentially expressed sequence of the present invention may be acomplete or partial RNA molecule.

Isolated DNA molecule able to be transcribed into the RNA molecule ofthe present invention are also encompassed herewith as well as vectors(including expression vectors) comprising the such DNA or RNA molecule.

The present invention also relates to libraries comprising at least oneisolated endogeneously and differentially expressed sequence identifiedherein (e.g., partial or complete RNA or DNA, substantially identicalsequences or substantially complementary sequences (e.g., probes) andfragments thereof (e.g., oligonucleotides)).

In accordance with the present invention, the isolated endogeneously anddifferentially expressed sequence may be selected, for example, from thegroup consisting of a polynucleotide which may consist in or comprise;

-   -   a) any one of SEQ ID NO.:1 to 33, SEQ ID NO.:85 or SEQ ID        NO.:86,    -   b) the open reading frame of any one of SEQ ID NO.:1 to 33, SEQ        ID NO.:85 or SEQ ID NO.:86,    -   c) a polynucleotide which may comprise a nucleotide sequence        substantially identical to a) or b), and;    -   d) a polynucleotide which may comprise a nucleotide sequence        substantially comlpementary to any one of a) to c),    -   e) fragments of any one of a) to d).

In a further aspect the present invention relates to a polypeptide whichmay be encoded by the isolated endogeneously and differentiallyexpressed sequence of the present invention.

In yet a further aspect the present invention relates to apolynucleotide able to encode a polypeptide of the present invention.Due to the degeneracy of the genetic code, it is to be understood hereinthat a multiplicity of polynucleotide sequence may encode the samepolypeptide sequence and thus are encompassed by the present invention.

Exemplary polypeptides may comprise a sequence selected from the groupconsisting of any one of SEQ ID NO.: 48 to 80, a polypeptide encoded bySEQ ID NO.:85 or SEQ ID NO.:86.

The present invention also relates to an isolated non-human orthologpolynucleotide sequence (involved in bone remodeling), the open readingframe of the non-human ortholog, substantially identical sequences,substantially complementary sequences, fragments and splice variantsthereof.

The present invention as well relates to an isolated polypeptide encodedby the non-human ortholog polynucleotide as well as biologically activeanalogs and biologically active fragments thereof.

Exemplary embodiments of non-human (e.g., mouse) orthologpolynucleotides encompassed herewith include, for example, SEQ IDNO.:35.

Exemplary embodiments of isolated polypeptide encoded by some non-humanorthologs identified herein include for example, a polypeptide such asSEQ ID NO.:82.

The present invention also more particularly relates, in an additionalaspect thereof, to an isolated polynucleotide which may bedifferentially expressed in differentiated osteoclast cell compared toundifferentiated human osteoclast precursor cell.

The isolated polynucleotide may comprise a member selected from thegroup consisting of;

-   -   a) a polynucleotide which may comprise any one of SEQ ID NO.:1        to SEQ ID NO.33, SEQ ID NO.:85 or SEQ ID NO.:86    -   b) a polynucleotide which may comprise the open reading frame of        any one of SEQ ID NO.:1 to SEQ ID NO.33, SEQ ID NO.:85 or SEQ ID        NO.:86;    -   c) a polynucleotide which may comprise a transcribed or        transcribable portion of any one of SEQ. ID. NOs:1 to SEQ ID        NO.33, SEQ ID NO.:85 or SEQ ID NO.:86, which may be, for        example, free of untranslated or untranslatable portion(s);    -   d) a polynucleotide which may comprise a translated or        translatable portion of any one of SEQ. ID. NOs:1 to SEQ ID        NO.33, SEQ ID NO.:85 or SEQ ID NO.:86 (e.g., coding portion),    -   e) a polynucleotide which may comprise a sequence substantially        identical (e.g., from about 50 to 100%, or about 60 to 100% or        about 70 to 100% or about 80 to 100% or about 85, 90, 95 to 100%        identical over the entire sequence or portion of sequences) to        a), b) c) or d),    -   f) a polynucleotide which may comprise a sequence substantially        complementary (e.g., from about 50 to 100%, or about 60 to 100%        or about 70 to 100% or about 80 to 100% or about 85, 90, 95 to        100% complementarity over the entire sequence or portion of        sequences) to a), b), c) or d) and;    -   g) a fragment of any one of a) to f)    -   h) including polynucleotides which consist in the above.

Exemplary polynucleotides fragments of those listed above comprisespolynucleotides of at least 10 nucleic acids which may be substantiallycomplementary to the nucleic acid sequence of any one of SEQ ID NO.: 1to 33, SEQ ID NO.:85 or SEQ ID NO.:86, for example, fragments selectedfrom the group consisting of any one of SEQ ID NO.: 42-45.

The present invention also relates to an isolated polynucleotideinvolved in osteoclast differentiation, the isolated polynucleotide maybe selected, for example, from the group consisting of;

-   -   a) a polynucleotide comprising any one of SEQ ID NO.: 1 to 33,        SEQ ID NO.:85 or SEQ ID NO.:86,    -   b) a polynucleotide comprising the open reading frame of any one        of SEQ ID NO.: 1 to 33, SEQ ID NO.:85 or SEQ ID NO.:86,    -   c) a polynucleotide which may comprise a transcribed or        transcribable portion of any one of SEQ. ID. NOs:1 to SEQ ID        NO.33, SEQ ID NO.:85 or SEQ ID NO.:86, which may be, for        example, free of untranslated or untranslatable portion(s);    -   d) a polynucleotide which may comprise a translated or        translatable portion of any one of SEQ. ID. NOs:1 to SEQ ID        NO.33, SEQ ID NO.:85 or SEQ ID NO.:86 (e.g., coding portion),    -   e) a polynucleotide substantially identical to a), b), c) or d);        and;    -   f) a sequence of at least 10 nucleic acids which may be        substantially complementary to the nucleic acid sequence of any        one of SEQ ID NO.:1 to 33, SEQ ID NO.:85 or SEQ ID NO.:86 or        more particularly of a), b), c) or d).

In accordance with the present invention the isolated polynucleotide maybe able to promote osteoclast differentiation (e.g., in a mammal ormammalian cell thereof), i.e, a positive regulator of osteoclastdifferenciation.

Further in accordance with the present invention, the isolatedpolynucleotide may be able to inhibit, prevent or lower osteoclastdifferentiation (e.g., in a mammal or mammalian cell thereof), i.e, anegative regulator of osteoclast differenciation.

In yet a further aspect, the present invention relates to an isolatedpolynucleotide which may be able to inhibit osteoclast differentiation(e.g., in a mammal or mammalian cell thereof). The polynucleotide may beselected, for example, from the group consisting of polynucleotideswhich may comprise a sequence of at least 10 nucleic acids which iscomplementary to the nucleic acid sequence of any one of NSEQ describedherein.

Suitable polynucleotides include, for example, a polynucleotide havingor comprising those which are selected from the group consisting of SEQID NO. 42 to 45.

Suitable polynucleotides may be those which may be able to inhibitosteoclast differentiation which has been induced by an inducer ofosteoclast differentiation such as those listed herein.

In accordance with the present invention, the polynucleotide may be, forexample, a RNA molecule, a DNA molecule, including those which arepartial or complete, single-stranded or double-stranded, hybrids, etc.

The present invention also relates to a vector (e.g., an expressionvector) comprising the polynucleotide of the present invention.

The present invention additionally relates in an aspect thereof to alibrary of polynucleotide sequences which may be differentiallyexpressed in a differentiated osteoclast cell compared to anundifferentiated osteoclast precursor cell. The library may comprise,for example, at least one member selected from the group consisting of

-   -   a) a polynucleotide which may comprise any one of SEQ ID NO.:1        to 33, SEQ ID NO.:85 or SEQ ID NO.:86,    -   b) a polynucleotide which may comprise the open reading frame of        any one of SEQ ID NO.:1 to 33, SEQ ID NO.:85 or SEQ ID NO.:86,    -   c) a polynucleotide which may comprise a transcribed or        transcribable portion of any one of SEQ. ID. NOs:1 to SEQ ID        NO.33, SEQ ID NO.:85 or SEQ ID NO.:86, which may be, for        example, free of untranslated or untranslatable portion(s);    -   d) a polynucleotide which may comprise a translated or        translatable portion of any one of SEQ. ID. NOs:1 to SEQ ID        NO.33, SEQ ID NO.:85 or SEQ ID NO.:86 (e.g., coding portion),    -   e) a polynucleotide which may comprise a sequence substantially        identical (e.g., from about 50 to 100%, or about 60 to 100% or        about 70 to 100% or about 80 to 100% or about 85, 90, 95 to 100%        identical over the entire sequence or portion of sequences) to        a), b), c) or d);    -   f) a polynucleotide which may comprise a sequence substantially        complementary (e.g., from about 50 to 100%, or about 60 to 100%        or about 70 to 100% or about 80 to 100% or about 85, 90, 95 to        100% complementarity over the entire sequence or portion of        sequences) to a), b), c) or d) and;    -   g) a fragment of any one of a) to d).

The present invention also relates to an expression library which maycomprise a library of polynucleotides described herein. In accordancewith the present invention, each of the polynucleotide may be containedwithin an expression vector.

Arrays and kits comprising a library of polynucleotide sequences(comprising at least one polynucleotide such as complementary sequences)of the present invention are also encompassed herewith.

The present invention also provides in an additional aspect, apharmaceutical composition for inhibiting osteoclast differentiation(bone resorption and bone resorption related diseases or disorders), thepharmaceutical composition may comprise, for example;

-   -   a) an isolated polynucleotide as defined herein (e.g., able to        inhibit osteoclast differentiation) and;    -   b) a pharmaceutically acceptable carrier.

The present invention also provides in yet an additional aspect, amethod for inhibiting osteoclast differentiation (e.g., for inhibitingbone resorption or for ameliorating bone resorption) in a mammal(individual) in need thereof (or in a mammalian cell), the method maycomprise administering an isolated polynucleotide (e.g., able to inhibitosteoclast differentiation) or a suitable pharmaceutical compositioncomprising such suitable polynucleotide.

In accordance with the present invention, the mammal in need may suffer,for example and without limitation, from a condition selected from thegroup consisting of osteoporosis, osteopenia, osteomalacia,hyperparathyroidism, hyperthyroidism, hypogonadism, thyrotoxicosis,systemic mastocytosis, adult hypophosphatasia, hyperadrenocorticism,osteogenesis imperfecta, Paget's disease, Cushing's disease/syndrome,Tumer syndrome, Gaucher disease, Ehlers-Danlos syndrome, Marfan'ssyndrome, Menkes' syndrome, Fanconi's syndrome, multiple myeloma,hypercalcemia, hypocalcemia, arthritides, periodontal disease, rickets(including vitamin D dependent, type I and II, and x-linkedhypophosphatemic rickets), fibrogenesis imperfecta ossium,osteosclerotic disorders such as pycnodysostosis and damage caused bymacrophage-mediated inflammatory processes, etc.

In a further aspect, the present invention relates to the use of anisolated polynucleotide (e.g., able to inhibit osteoclastdifferentiation) for the preparation of a medicament for the treatmentof a bone resorption disease.

The present invention in another aspect thereof, provides apharmaceutical composition for promoting osteoclast differentiation in amammal in need thereof. The pharmaceutical composition may comprise, forexample;

-   -   a. an isolated polynucleotide (e.g., able to promote osteoclast        differentiation) and;    -   b. a pharmaceutically acceptable carrier.

The present invention also further provides a method for promotingosteoclast differentiation in a mammal in need thereof (or in amammalian cell), the method may comprise, for example, administering anisolated polynucleotide (e.g., able to promote osteoclastdifferentiation) or a suitable pharmaceutical composition as describedabove.

The present invention additionally relates to the use of an isolatedpolynucleotide (e.g., able to promote osteoclast differentiation) forthe preparation of a medicament for the treatment of a diseaseassociated with insufficient bone resorption (e.g., hyperostosis) orexcessive bone growth.

The present invention also relates to the use of at least onepolynucleotide which may be selected from the group consisting of;

-   -   a) a polynucleotide comprising any one of SEQ ID NO.:1 to 33,        SEQ ID NO.:85 or SEQ ID NO.:86,    -   b) a polynucleotide comprising the open reading frame of any one        of SEQ ID NO.:1 to 33, SEQ ID NO.:85 or SEQ ID NO.:86,    -   c) a polynucleotide which may comprise a transcribed or        transcribable portion of any one of SEQ. ID. NOs:1 to SEQ ID        NO.33, SEQ ID NO.:85 or SEQ ID NO.:86, which may be, for        example, free of untranslated or untranslatable portion(s);    -   d) a polynucleotide which may comprise a translated or        translatable portion of any one of SEQ. ID. NOs:1 to SEQ ID        NO.33, SEQ ID NO.:85 or SEQ ID NO.:86 (e.g., coding portion),    -   e) a polynucleotide comprising a sequence substantially        identical (e.g., from about 50 to 100%, or about 60 to 100% or        about 70 to 100% or about 80 to 100% or about 85, 90, 95 to 100%        identical over the entire sequence or portion of sequences) to        a), b), c) or d);    -   f) a polynucleotide comprising a sequence substantially        complementary (e.g., from about 50 to 100%, or about 60 to 100%        or about 70 to 100% or about 80 to 100% or about 85, 90, 95 to        100% complementarity over the entire sequence or portion of        sequences) to a), b), c) or d);    -   g) a fragment of any one of a) to f) and;    -   h) a library comprising any one of a) to g)

in the diagnosis of a condition related to bone remodeling (a bonedisease).

Also encompassed by the present invention are kits for the diagnosis ofa condition related to bone remodeling. The kit may comprise apolynucleotide as described herein.

The present invention also provides in an additional aspect, an isolatedpolypeptide (polypeptide sequence) involved in osteoclastdifferentiation (in a mammal or a mammalian cell thereof). Thepolypeptide may comprise (or consist in) a sequence selected from thegroup consisting of;

-   -   a) any one of SEQ ID NO.: 48 to 80,    -   b) a polypeptide able to be encoded and/or encoded by any one of        SEQ ID NO.:1 to 33, SEQ ID NO.:85 or SEQ ID NO.:86 (their coding        portion)    -   c) a biologically active fragment of any one of a) or b),    -   d) a biologically active analog of any one of a) or b).

In accordance with the present invention, the biologically active analogmay comprise, for example, at least one amino acid substitution(conservative or non conservative) compared to the original sequence. Inaccordance with the present invention, the analog may comprise, forexample, at least one amino acid substitution, deletion or insertion inits amino acid sequence.

The substitution may be conservative or non-conservative. Thepolypeptide analog may be a biologically active analog or an immunogenicanalog which may comprise, for example, at least one amino acidsubstitution (conservative or non conservative), for example, 1 to 5, 1to 10, 1 to 15, 1 to 20, 1 to 50 etc. (including any number therebetween) compared to the original sequence. An immunogenic analog maycomprise, for example, at least one amino acid substitution compared tothe original sequence and may still be bound by an antibody specific forthe original sequence.

In accordance with the present invention, a polypeptide fragment maycomprise, for example, at least 6 consecutive amino acids, at least 8consecutive amino acids or more of an amino acid sequence describedherein.

In yet a further aspect, the present invention provides a pharmaceuticalcomposition which may comprise, for example a polypeptide as describedherein and a pharmaceutically acceptable carrier.

Methods for modulating osteoclast differentiation in a mammal in needthereof (or in a mammalian cell) are also provided by the presentinvention, which methods may comprise administering an isolatedpolypeptide (e.g., able to promote osteoclast differentiation) orsuitable pharmaceutical composition described herein.

In additional aspects, the present invention relates to the use of anisolated polypeptide (e.g., able to promote osteoclast differentiation)for the preparation of a medicament for the treatment of a diseaseassociated with insufficient bone resorption.

Methods for ameliorating bone resorption in an individual in needthereof are also encompassed herewith, which method may comprise, forexample, administering an isolated polypeptide (e.g., able to inhibitosteoclast differentiation) or suitable pharmaceutical compositionswhich may comprise such polypeptide.

In accordance with the present invention, the mammal may suffer, forexample, from a condition selected from the group consisting ofosteoporosis, osteopenia, osteomalacia, hyperparathyroidism,hyperthyroidism, hypogonadism, thyrotoxicosis, systemic mastocytosis,adult hypophosphatasia, hyperadrenocorticism, osteogenesis imperfecta,Paget's disease, Cushing's disease/syndrome, Tumer syndrome, Gaucherdisease, Ehlers-Danlos syndrome, Marfan's syndrome, Menkes' syndrome,Fanconi's syndrome, multiple myeloma, hypercalcemia, hypocalcemia,arthritides, periodontal disease, rickets (including vitamin Ddependent, type I and II, and x-linked hypophosphatemic rickets),fibrogenesis imperfecta ossium, osteosclerotic disorders such aspycnodysostosis and damage caused by macrophage-mediated inflammatoryprocesses, etc.

In yet a further aspect, the present invention relates to the use of apolypeptide able to inhibit osteoclast differentiation in thepreparation of a medicament for the treatment of a bone resorptiondisease in an individual in need thereof.

The present invention also relates to a compound and the use of acompound able to inhibit (e.g., in an osteoclast precursor cell) theactivity or expression of a polypeptide which may be selected, forexample, from the group consisting of SEQ ID NO.: 48 to 80 or apolypeptide encoded by SEQ ID NO.:85 or SEQ ID NO.:86, in thepreparation of a medicament for the treatment of a bone disease in anindividual in need thereof.

In yet an additional aspect, the present invention relates to a methodof diagnosing a condition related to a bone resorption disorder ordisease in an individual in need thereof. The method may comprise, forexample, quantifying a polynucleotide described herein, such as, forexample, polynucleotide selected from the group consisting of thosecomprising or consisting of (a) SEQ ID NO.:1 to 33, SEQ ID NO.:85 or SEQID NO.:86, (b) a polynucleotide which may comprise the open readingframe of SEQ ID NO.: 1 to 33, SEQ ID NO.:85 or SEQ ID NO.:86, (c) apolynucleotide which may comprise a transcribed or transcribable portionof any one of SEQ. ID. NOs:1 to SEQ ID NO.33, SEQ ID NO.:85 or SEQ IDNO.:86 (d) a polynucleotide which may comprise a translated ortranslatable portion of any one of SEQ. ID. NOs:1 to SEQ ID NO.33, SEQID NO.:85 or SEQ ID NO.:86; (e) substantially identical sequences of anyone of (a) to (d); (f) substantially complementary sequences of any oneof (a) to (e), or a polypeptide sequence which may be selected, forexample, from the group consisting of SEQ ID NO.: 48 to 80 or apolypeptide encoded by SEQ ID NO.:85 or SEQ ID NO.:86, and analogsthereof in a sample from the individual compared to a standard or normalvalue.

The present invention also relates to an assay and method foridentifying a gene and/or protein involved in bone remodeling. The assayand method may comprise silencing an endogenous gene of an osteoclastcell and providing the cell with a candidate gene (or protein). Acandidate gene (or protein) positively involved in bone remodeling maybe identified by its ability to complement the silenced endogenous gene.For example, a candidate gene involved in osteoclast differentiationprovided to a cell for which an endogenous gene has been silenced, mayenable the cell to differentiate in the presence of an inducer such as,for example, RANKL.

The present invention further relates to a cell expressing an exogenousform of any one of the polypeptide (including variants, analogs etc.) orpolynucleotide of the present invention (including substantiallyidentical sequences, substantially complementary sequences, fragments,variants, orthologs, etc).

In accordance with the present invention, the cell may be for example, abone cell. Also in accordance with the present invention, the cell maybe an osteoclast (at any level of differentiation).

As used herein the term “exogenous form” is to be understood herein as aform which is not naturally expressed by the cell in question.

In a further aspect, the present invention relates to an antibody (e.g.,isolated antibody), or antigen-binding fragment thereof, that mayspecifically bind to a protein or polypeptide described herein. Theantibody may be, for example, a monoclonal antibody, a polyclonalantibody an antibody generated using recombinant DNA technologies. Theantibody may originate for example, from a mouse, rat or any othermammal.

The antibody may also be a human antibody which may be obtained, forexample, from a transgenic non-human mammal capable of expressing humanIg genes. The antibody may also be a humanised antibody which maycomprise, for example, one or more complementarity determining regionsof non-human origin. It may also comprise a surface residue of a humanantibody and/or framework regions of a human antibody. The antibody mayalso be a chimeric antibody which may comprise, for example, variabledomains of a non-human antibody and constant domains of a humanantibody.

Suitable antibodies may also include, for example, an antigen-bindingfragment, an Fab fragment; an F(ab′)₂ fragment, and Fv fragment; or asingle-chain antibody comprising an antigen-binding fragment (e.g., asingle chain Fv).

The antibody of the present invention may be mutated and selected basedon an increased affinity and/or specificity for one of a polypeptidedescribed herein and/or based on a reduced immunogenicity in a desiredhost.

The antibody may further comprise a detectable label attached thereto.

The present invention further relates to a method of producingantibodies able to bind to one of a polypeptide, polypeptide fragments,or polypeptide analogs described herein, the method may comprise:

-   -   a) immunizing a mammal (e.g., mouse, a transgenic mammal capable        of producing human Ig, etc.) with a suitable amount of a PSEQ        described herein including, for example, a polypeptide fragment        comprising at least 6 consecutive amino acids of a PSEQ;    -   b) collecting the serum from the mammal; and    -   c) isolating the polypeptide-specific antibodies from the serum        of the mammal.

The method may further comprise the step of administering a second doseto the animal.

The present invention also relates to a method of producing a hybridomawhich secretes an antibody that binds to a polypeptide described herein,the method may comprise:

-   -   a) immunizing a mammal (e.g., mouse, a transgenic mammal capable        of producing human Ig, etc.) with a suitable amount of a PSEQ        thereof;    -   b) obtaining lymphoid cells from the immunized animal obtained        from (a);    -   c) fusing the lymphoid cells with an immortalizing cell to        produce hybrid cells; and    -   d) selecting hybrid cells which produce antibody that        specifically binds to a PSEQ thereof.

The present invention further relates to a method of producing anantibody that binds to one of the polypeptide described herein, themethod may comprise:

-   -   a) synthesizing a library of antibodies (antigen binding        fragment) on phage or ribosomes;    -   b) panning the library against a sample by bringing the phage or        ribosomes into contact with a composition comprising a        polypeptide or polypeptide fragment described herein;    -   c) isolating phage which binds to the polypeptide or polypeptide        fragment, and;    -   d) obtaining an antibody from the phage or ribosomes.

The antibody of the present invention may thus be obtained, for example,from a library (e.g., bacteriophage library) which may be prepared, forexample, by

-   -   a) extracting cells which are responsible for production of        antibodies from a host mammal;    -   b) isolating RNA from the cells of (a);    -   c) reverse transcribing mRNA to produce cDNA;    -   d) amplifying the cDNA using a (antibody-specific) primer; and    -   e) inserting the cDNA of (d) into a phage display vector or        ribosome display cassette such that antibodies are expressed on        the phage or ribosomes.

The host animal may be immunized with polypeptide and/or a polypeptidefragment and/or analog described herein to induce an immune responseprior to extracting the cells which are responsible for production ofantibodies.

The present invention also relates to a kit for specifically assaying apolypeptide described herein, the kit may comprise, for example, anantibody or antibody fragment capable of binding specifically to thepolypeptide described herein.

The present invention further contemplates antibodies that may bind toPSEQ. Suitable antibodies may bind to unique antigenic regions orepitopes in the polypeptides, or a portion thereof. Epitopes andantigenic regions useful for generating antibodies may be found withinthe proteins, polypeptides or peptides by procedures available to one ofskill in the art. For example, short, unique peptide sequences may beidentified in the proteins and polypeptides that have little or nohomology to known amino acid sequences. Preferably the region of aprotein selected to act as a peptide epitope or antigen is not entirelyhydrophobic; hydrophilic regions are preferred because those regionslikely constitute surface epitopes rather than internal regions of theproteins and polypeptides. These surface epitopes are more readilydetected in samples tested for the presence of the proteins andpolypeptides. Such antibodies may include, but are not limited to,polyclonal, monoclonal, chimeric, and single chain antibodies, Fabfragments, and fragments produced by a Fab expression library. Theproduction of antibodies is well known to one of skill in the art.

Peptides may be made by any procedure known to one of skill in the art,for example, by using in vitro translation or chemical synthesisprocedures. Short peptides which provide an antigenic epitope but whichby themselves are too small to induce an immune response may beconjugated to a suitable carrier. Suitable carriers and methods oflinkage are well known in the art. Suitable carriers are typically largemacromolecules such as proteins, polysaccharides and polymeric aminoacids. Examples include serum albumins, keyhole limpet hemocyanin,ovalbumin, polylysine and the like. One of skill in the art may useavailable procedures and coupling reagents to link the desired peptideepitope to such a carrier. For example, coupling reagents may be used toform disulfide linkages or thioether linkages from the carrier to thepeptide of interest. If the peptide lacks a disulfide group, one may beprovided by the addition of a cysteine residue. Alternatively, couplingmay be accomplished by activation of carboxyl groups.

The minimum size of peptides useful for obtaining antigen specificantibodies may vary widely. The minimum size must be sufficient toprovide an antigenic epitope that is specific to the protein orpolypeptide. The maximum size is not critical unless it is desired toobtain antibodies to one particular epitope. For example, a largepolypeptide may comprise multiple epitopes, one epitope beingparticularly useful and a second epitope being immunodominant.Typically, antigenic peptides selected from the present proteins andpolypeptides will range from 5 to about 100 amino acids in length. Moretypically, however, such an antigenic peptide will be a maximum of about50 amino acids in length, and preferably a maximum of about 30 aminoacids. It is usually desirable to select a sequence of about 6, 8, 10,12 or 15 amino acids, up to about 20 or 25 amino acids.

Amino acid sequences comprising useful epitopes may be identified in anumber of ways. For example, preparing a series of short peptides thattaken together span the entire protein sequence may be used to screenthe entire protein sequence. One of skill in the art may routinely testa few large polypeptides for the presence of an epitope showing adesired reactivity and also test progressively smaller and overlappingfragments to identify a preferred epitope with the desired specificityand reactivity.

Antigenic polypeptides and peptides are useful for the production ofmonoclonal and polyclonal antibodies. Antibodies to a polypeptideencoded by the polynucleotides of NSEQ, polypeptide analogs or portionsthereof, may be generated using methods that are well known in the art.Such antibodies may include, but are not limited to, polyclonal,monoclonal, chimeric, and single chain antibodies, Fab fragments, andfragments produced by a Fab expression library. Neutralizing antibodies,such as those that inhibit dimer formation, are especially preferred fortherapeutic use. Monoclonal antibodies may be prepared using anytechnique that provides for the production of antibody molecules bycontinuous cell lines in culture. These include, but are not limited to,the hybridoma, the human B-cell hybridoma, and the EBV-hybridomatechniques. In addition, techniques developed for the production ofchimeric antibodies may be used. Alternatively, techniques described forthe production of single chain antibodies may be employed. Fabs that maycontain specific binding sites for a polypeptide encoded by thepolynucleotides of NSEQ, or a portion thereof, may also be generated.Various immunoassays may be used to identify antibodies having thedesired specificity. Numerous protocols for competitive binding orimmunoradiometric assays using either polyclonal or monoclonalantibodies with established specificities are well known in the art.

To obtain polyclonal antibodies, a selected animal may be immunized witha protein or polypeptide. Serum from the animal may be collected andtreated according to known procedures. Polyclonal antibodies to theprotein or polypeptide of interest may then be purified by affinitychromatography. Techniques for producing polyclonal antisera are wellknown in the art.

Monoclonal antibodies (MAbs) may be made by one of several proceduresavailable to one of skill in the art, for example, by fusing antibodyproducing cells with immortalized cells and thereby making a hybridoma.The general methodology for fusion of antibody producing B cells to animmortal cell line is well within the province of one skilled in theart. Another example is the generation of MAbs from mRNA extracted frombone marrow and spleen cells of immunized animals using combinatorialantibody library technology.

One drawback of MAbs derived from animals or from derived cell lines isthat although they may be administered to a patient for diagnostic ortherapeutic purposes, they are often recognized as foreign antigens bythe immune system and are unsuitable for continued use. Antibodies thatare not recognized as foreign antigens by the human immune system havegreater potential for both diagnosis and treatment. Methods forgenerating human and humanized antibodies are now well known in the art.

Chimeric antibodies may be constructed in which regions of a non-humanMAb are replaced by their human counterparts. A preferred chimericantibody is one that has amino acid sequences that comprise one or morecomplementarity determining regions (CDRs) of a non-human Mab that bindsto a polypeptide encoded by the polynucleotides of NSEQ, or a portionthereof, grafted to human framework (FW) regions. Methods for producingsuch antibodies are well known in the art. Amino acid residuescorresponding to CDRs and FWs are known to one of average skill in theart.

A variety of methods have been developed to preserve or to enhanceaffinity for antigen of antibodies comprising grafted CDRs. One way isto include in the chimeric antibody the foreign framework residues thatinfluence the conformation of the CDR regions. A second way is to graftthe foreign CDRs onto human variable domains with the closest homologyto the foreign variable region. Thus, grafting of one or more non-humanCDRs onto a human antibody may also involve the substitution of aminoacid residues which are adjacent to a particular CDR sequence or whichare not contiguous with the CDR sequence but which are packed againstthe CDR in the overall antibody variable domain structure and whichaffect the conformation of the CDR. Humanized antibodies of theinvention therefore include human antibodies which comprise one or morenon-human CDRs as well as such antibodies in which additionalsubstitutions or replacements have been made to preserve or enhancebinding characteristics.

Chimeric antibodies of the invention also include antibodies that havebeen humanized by replacing surface-exposed residues to make the MAbappear human. Because the internal packing of amino acid residues in thevicinity of the antigen-binding site remains unchanged, affinity ispreserved. Substitution of surface-exposed residues of a polypeptideencoded by the polynucleotides of NSEQ (or a portion thereof)-antibodyaccording to the invention for the purpose of humanization does not meansubstitution of CDR residues or adjacent residues that influenceaffinity for a polypeptide encoded by the polynucleotides of NSEQ, or aportion thereof.

Chimeric antibodies may also include antibodies where some or allnon-human constant domains have been replaced with human counterparts.This approach has the advantage that the antigen-binding site remainsunaffected. However, significant amounts of non-human sequences may bepresent where variable domains are derived entirely from non-humanantibodies.

Antibodies of the invention include human antibodies (e.g., humanized)that are antibodies consisting essentially of human sequences. Humanantibodies may be obtained from phage display libraries whereincombinations of human heavy and light chain variable domains aredisplayed on the surface of filamentous phage. Combinations of variabledomains are typically displayed on filamentous phage in the form of Fab′s or scFvs. The library may be screened for phage bearing combinationsof variable domains having desired antigen-binding characteristics.Preferred variable domain combinations are characterized by highaffinity for a polypeptide encoded by the polynucleotides of NSEQ, or aportion thereof. Preferred variable domain combinations may also becharacterized by high specificity for a polypeptide encoded by thepolynucleotides of NSEQ, or a portion thereof, and littlecross-reactivity to other related antigens. By screening from very largerepertoires of antibody fragments, (2−10×10¹⁰) a good diversity of highaffinity Mabs may be isolated, with many expected to have sub-nanomolaraffinities for a polypeptide encoded by the polynucleotides of NSEQ, ora portion thereof.

Alternatively, human antibodies may be obtained from transgenic animalsinto which un-rearranged human Ig gene segments have been introduced andin which the endogenous mouse Ig genes have been inactivated. Preferredtransgenic animals contain very large contiguous Ig gene fragments thatare over 1 Mb in size but human polypeptide-specific Mabs of moderateaffinity may be raised from transgenic animals containing smaller geneloci. Transgenic animals capable of expressing only human Ig genes mayalso be used to raise polyclonal antiserum comprising antibodies solelyof human origin.

Antibodies of the invention may include those for which bindingcharacteristics have been improved by direct mutation or by methods ofaffinity maturation. Affinity and specificity may be modified orimproved by mutating CDRs and screening for antigen binding sites havingthe desired characteristics. CDRs may be mutated in a variety of ways.One way is to randomize individual residues or combinations of residuesso that in a population of otherwise identical antigen binding sites,all twenty amino acids may be found at particular positions.Alternatively, mutations may be induced over a range of CDR residues byerror prone PCR methods. Phage display vectors containing heavy andlight chain variable region gene may be propagated in mutator strains ofE. coli. These methods of mutagenesis are illustrative of the manymethods known to one of skill in the art.

Antibodies of the invention may include complete anti-polypeptideantibodies as well as antibody fragments and derivatives that comprise abinding site for a polypeptide encoded by the polynucleotides of NSEQ,or a portion thereof. Derivatives are macromolecules that comprise abinding site linked to a functional domain. Functional domains mayinclude, but are not limited to signalling domains, toxins, enzymes andcytokines.

The antibodies obtained by the means described herein may be useful fordetecting proteins, variant and derivative polypeptides in specifictissues or in body fluids. Moreover, detection of aberrantly expressedproteins or protein fragments is probative of a disease state. Forexample, expression of the present polypeptides encoded by thepolynucleotides of NSEQ, or a portion thereof, may indicate that theprotein is being expressed at an inappropriate rate or at aninappropriate developmental stage. Hence, the present antibodies may beuseful for detecting diseases associated with protein expression fromNSEQs disclosed herein.

A variety of protocols for measuring polypeptides, including ELISAs,RIAs, and FACS, are well known in the art and provide a basis fordiagnosing altered or abnormal levels of expression. Standard values forpolypeptide expression are established by combining samples taken fromhealthy subjects, preferably human, with antibody to the polypeptideunder conditions for complex formation. The amount of complex formationmay be quantified by various methods, such as photometric means.Quantities of polypeptide expressed in disease samples may be comparedwith standard values. Deviation between standard and subject valuesmayestablish the parameters for diagnosing or monitoring disease.

Design of immunoassays is subject to a great deal of variation and avariety of these are known in the art. Immunoassays may use a monoclonalor polyclonal antibody reagent that is directed against one epitope ofthe antigen being assayed. Alternatively, a combination of monoclonal orpolyclonal antibodies may be used which are directed against more thanone epitope. Protocols may be based, for example, upon competition whereone may use competitive drug screening assays in which neutralizingantibodies capable of binding a polypeptide encoded by thepolynucleotides of NSEQ, or a portion thereof, specifically compete witha test compound for binding the polypeptide. Alternatively one may use,direct antigen-antibody reactions or sandwich type assays and protocolsmay, for example, make use of solid supports or immunoprecipitation.Furthermore, antibodies may be labelled with a reporter molecule foreasy detection. Assays that amplify the signal from a bound reagent arealso known. Examples include immunoassays that utilize avidin andbiotin, or which utilize enzyme-labelled antibody or antigen conjugates,such as ELISA assays.

Kits suitable for immunodiagnosis and containing the appropriatelabelled reagents include antibodies directed against the polypeptideprotein epitopes or antigenic regions, packaged appropriately with theremaining reagents and materials required for the conduct of the assay,as well as a suitable set of assay instructions.

The present invention therefore provides a kit for specifically assayinga polypeptide described herein, the kit may comprise, for example, anantibody or antibody fragment capable of binding specifically to thepolypeptide described herein.

In accordance with the present invention, the kit may be a diagnostickit, which may comprise:

-   -   a) one or more antibodies described herein; and    -   b) a detection reagent which may comprise a reporter group.

In accordance with the present invention, the antibodies may beimmobilized on a solid support. The detection reagent may comprise, forexample, an anti-immunoglobulin, protein G, protein A or lectin etc. Thereporter group may be selected, without limitation, from the groupconsisting of radioisotopes, fluorescent groups, luminescent groups,enzymes, biotin and dye particles.

In an additional aspect, the present invention provides a method foridentifying an inhibitory compound (inhibitor, antagonist) which may beable to impair the function (activity) or expression of a polypeptidedescribed herein, such as, for example, those which may be selected fromthe group consisting of SEQ ID NO.: 48 to 80 or a polypeptide encoded bySEQ ID NO.:85 or SEQ ID NO.:86, and analogs thereof. The method maycomprise contacting the polypeptide or a cell expressing the polypeptidewith a candidate compound and measuring the function (activity) orexpression of the polypeptide. A reduction in the function or activityof the polypeptide (compared to the absence of the candidate compound)may positively identify a suitable inhibitory compound.

In accordance with the present invention, the impaired function oractivity may be associated with a reduced ability of the polypeptide topromote osteoclast differentiation, such as osteoclast differentiationinduced by an inducer described herein or known in the art.

In accordance with the present invention the cell may not naturally(endogenously) express (polypeptide may substantially be unexpressed ina cell) the polypeptide or analog or alternatively, the expression of anaturally expressed polypeptide analog may be repressed.

For example, suitable method of screening for an inhibitor of SEQ IDNO.:1, may comprise repressing the expression of the mouse ortholog SEQID NO.:35 in a mouse osteoclast cell and evaluating differentiation ofthe osteoclast cell comprising SEQ ID NO.:1 in the presence or absenceof a candidate inhibitor and for example, an inducer of osteoclastdifferentiation (e.g., RANKL).

The present invention also provides a method for identifying aninhibitory compound (inhibitor, antagonist) able to impair the function(activity) or expression of a polypeptide such as, for example SEQ IDNO.: 1 or SEQ ID NO.:2. The method may comprise, for example, contactingthe (isolated) polypeptide or a cell expressing the polypeptide with acandidate compound and measuring the function (activity) or expressionof the polypeptide. A reduction in the function or activity of thepolypeptide (compared to the absence of the candidate compound) may thuspositively identify a suitable inhibitory compound.

In accordance with the present invention, the impaired function oractivity may be associated, for example, with a reduced ability of thepolypeptide to inhibit or promote osteoclast differentiation.

The cell used to carry the screening test may not naturally(endogenously) express the polypeptide or analogs, or alternatively theexpression of a naturally expressed polypeptide analog may be repressed.

The present invention also relates to a method of identifying a positiveor a negative regulator of osteoclast differentiation. The method maycomprise, for example, performing a knockdown effect as describedherein. The method may more particularly comprise a) providing anosteoclast cell with a compound (e.g., siRNA) able to specificallyinhibit a target sequence (e.g., a polynucleotide or polypeptide asdescribed herein), b) inducing differentiation (e.g., with an inducersuch as, for example, RANKL) and c) determining the level ofdifferentiation of the osteoclast cell (e.g., measuring the number ofdifferentiated cells, their rate of differentiation, specific marker ofdifferentiation etc).

Upon inhibition of a positive regulator, the levels of osteoclastdifferentiation will appear lowered. Upon inhibition of a negativeregulator, the level of osteoclast differentiation will appearincreased.

Another method of identifying a positive or a negative regulator ofosteoclast differentiation is to a) provide a cell with one of a targetsequence described herein (polypeptide or polynucleotide able to expressa polypeptide) b) to induce differentiation (e.g., with an inducer suchas, for example, RANKL) and c) to determine the level of differentiationof the osteoclast cell (e.g., measuring the number of differentiatedcells, their rate of differentiation, specific marker of differentiationetc).

A cell provided with a positive regulator of osteoclast differentiationmay have an increased level of differentiation. A cell provided with anegative regulator of osteoclast differentiation may have a decreasedlevel of differentiation.

The present invention also provides a method of identifying a compoundcapable of interfering with osteoclast differentiation, the method maycomprise contacting a cell including therein a non-endogenouspolynucleotide sequence comprising any one of SEQ ID NO.:1 to 33, 85 or86 (a coding portion) and quantifying (e.g. the number of)differentiated osteoclasts. A reduction in osteoclast differentiation inthe presence of the compound in comparison to the absence of thecompound may be indicative of an antagonist of osteoclastdifferentiation, while an increase in osteoclast differentiation in thepresence of the compound in comparison to the absence of the compoundmay be indicative of an agonist of osteoclast differentiation.

In accordance with the present invention, the cell may also comprise anendogenous form of a polynucleotide.

As used herein the term “endogenous” means a substance that naturallyoriginates from within an organism, tissue or cell. The term “endogenouspolynucleotide” refers to a chromosomal form of a polynucleotide or RNAversion (hnRNA, mRNA) produced by the chromosal form of thepolynucleotide. The term “endogenous polypeptide” refers to the form ofthe protein encoded by an “endogenous polynucleotide”.

As used herein the term “non-endogenous” or “exogenous” is used inopposition to “endogenous” in that the substance is provided from anexternal source although it may be introduced within the cell. The term“non-endogenous polynucleotide” refers to a synthetic polynucleotideintroduced within the cell and include for example and withoutlimitation, a vector comprising a sequence of interest, a syntheticmRNA, an oligonucleotide comprising a NSEQ etc. The term “non-endogenouspolypeptide” refers to the form of the protein encoded by an“non-endogenous polynucleotide”.

The present invention also relate to a method of identifying a compoundcapable of interfering with osteoclast differentiation, the method maycomprise contacting a cell including therein a non-endogenouspolypeptide sequence comprising any one of SEQ ID NO.: 48 to 80 andquantifying (e.g. the number of) differentiated osteoclasts. A reductionin osteoclast differentiation in the presence of the compound incomparison to the absence of the compound may be indicative of anantagonist of osteoclast differentiation while an increase in osteoclastdifferentiation in the presence of the compound in comparison to theabsence of the compound may be indicative of an agonist of osteoclastdifferentiation.

As used herein the term “sequence identity” relates to (consecutive)nucleotides of a nucleotide sequence which with reference to an originalnucleotide sequence. The identity may be compared over a region or overthe total sequence of a nucleic acid sequence.

Thus, “identity” may be compared, for example, over a region of 3, 4, 5,10, 19, 20 nucleotides or more (and any number there between). It is tobe understood herein that gaps of non-identical nucleotides may be foundbetween identical nucleic acids. For example, a polynucleotide may have100% identity with another polynucleotide over a portion thereof.However, when the entire sequence of both polynucleotides is compared,the two polynucleotides may have 50% of their overall (total) sequenceidentical to one another.

Polynucleotides of the present invention or portion thereof having fromabout 50 to about 100%, or about 60 to about 100% or about 70 to about100% or about 80 to about 100% or about 85%, about 90%, about 95% toabout 100% sequence identity with an original polynucleotide areencompassed herewith. It is known by those of skill in the art, that apolynucleotide having from about 50% to 100% identity may function(e.g., anneal to a substantially complementary sequence) in a mannersimilar to an original polynucleotide and therefore may be used inreplacement of an original polynucleotide. For example a polynucleotide(a nucleic acid sequence) may comprise or have from about 50% to 100%identity with an original polynucleotide over a defined region and maystill work as efficiently or sufficiently to achieve the presentinvention.

Percent identity may be determined, for example, with an algorithm GAP,BESTFIT, or FASTA in the Wisconsin Genetics Software Package Release7.0, using default gap weights.

As used herein the terms “sequence complementarity” refers to(consecutive) nucleotides of a nucleotide sequence which arecomplementary to a reference (original) nucleotide sequence. Thecomplementarity may be compared over a region or over the total sequenceof a nucleic acid sequence.

Polynucleotides of the present invention or portion thereof having fromabout 50 to about 100%, or about 60 to about 100% or about 70 to about100% or about 80 to about 100% or about 85%, about 90%, about 95% toabout 100% sequence complementarity with an original polynucleotide arethus encompassed herewith. It is known by those of skill in the art,that an polynucleotide having from about 50% to 100% complementaritywith an original sequence may anneal to that sequence in a mannersufficient to carry out the present invention (e.g., inhibit expressionof the original polynucleotide).

An “analogue” is to be understood herein as a molecule having abiological activity and chemical structure similar to that of apolypeptide described herein. An “analogue” may have sequence similaritywith that of an original sequence or a portion of an original sequenceand may also have a modification of its structure as discussed herein.For example, an “analogue” may have at least 90% sequence similaritywith an original sequence or a portion of an original sequence. An“analogue” may also have, for example; at least 70% or even 50% sequencesimilarity (or less, i.e., at least 40%) with an original sequence or aportion of an original sequence.

Also, an “analogue” with reference to a polypeptide may have, forexample, at least 50% sequence similarity to an original sequence with acombination of one or more modification in a backbone or side-chain ofan amino acid, or an addition of a group or another molecule, etc.

“Polynucleotide” generally refers to any polyribonucleotide orpolydeoxyribo-nucleotide, which may be unmodified RNA or DNA, ormodified RNA or DNA. “Polynucleotides” include, without limitationsingle- and double-stranded DNA, DNA that is a mixture of single- anddouble-stranded regions, single- and double-stranded RNA, and RNA thatis a mixture of single- and double-stranded regions, hybrid moleculescomprising DNA and RNA that may be single-stranded or, more typically,double-stranded or a mixture of single- and double-stranded regions. Inaddition, “polynucleotide” refers to triple-stranded regions comprisingRNA or DNA or both RNA and DNA. The term polynucleotide also includesDNAs or RNAs containing one or more modified bases and DNAs or RNAs withbackbones modified for stability or for other reasons. “Modified” basesinclude, for example, tritylated bases and unusual bases such asinosine. A variety of modifications may be made to DNA and RNA; thus“polynucleotide” embraces chemically, enzymatically or metabolicallymodified forms of polynucleotides as typically found in nature, as wellas the chemical forms of DNA and RNA characteristic of viruses andcells. “Polynucleotide” includes but is not limited to linear andend-closed molecules. “Polynucleotide” also embraces relatively shortpolynucleotides, often referred to as oligonucleotides.

“Polypeptides” refers to any peptide or protein comprising two or moreamino acids joined to each other by peptide bonds or modified peptidebonds (i.e., peptide isosteres). “Polypeptide” refers to both shortchains, commonly referred as peptides, oligopeptides or oligomers, andto longer chains generally referred to as proteins. As described above,polypeptides may contain amino acids other than the 20 gene-encodedamino acids.

As used herein the term “polypeptide analog” relates to mutants,variants, chimeras, fusions, deletions, additions and any other type ofmodifications made relative to a given polypeptide.

As used herein the term “biologically active” refers to a variant orfragment which retains some or all of the biological activity of thenatural polypeptide, i.e., to be able to promote or inhibit osteoclastdifferentiation. Polypeptides or fragments of the present invention mayalso include “immunologically active” polypeptides or fragments.“Immunologically active polypeptides or fragments may be useful forimmunization purposes (e.g. in the generation of antibodies).

Thus, biologically active polypeptides in the form of the originalpolypeptides, fragments (modified or not), analogues (modified or not),derivatives (modified or not), homologues, (modified or not) of thepolypeptides described herein are encompassed by the present invention.

Therefore, any polypeptide having a modification compared to an originalpolypeptide which does not destroy significantly a desired biologicalactivity is encompassed herein. It is well known in the art, that anumber of modifications may be made to the polypeptides of the presentinvention without deleteriously affecting their biological activity.These modifications may, on the other hand, keep or increase thebiological activity of the original polypeptide or may optimize one ormore of the particularity (e.g. stability, bioavailability, etc.) of thepolypeptides of the present invention which, in some instance might bedesirable. Polypeptides of the present invention may comprise forexample, those containing amino acid sequences modified either bynatural processes, such as posttranslational processing, or by chemicalmodification techniques which are known in the art. Modifications mayoccur anywhere in a polypeptide including the polypeptide backbone, theamino acid side-chains and the amino- or carboxy-terminus. It will beappreciated that the same type of modification may be present in thesame or varying degrees at several sites in a given polypeptide. Also, agiven polypeptide may contain many types of modifications. It is to beunderstood herein that more than one modification to the polypeptidesdescribed herein are encompassed by the present invention to the extentthat the biological activity is similar to the original (parent)polypeptide.

As discussed above, polypeptide modification may comprise, for example,amino acid insertion (i.e., addition), deletion and substitution (i.e.,replacement), either conservative or non-conservative (e.g., D-aminoacids, desamino acids) in the polypeptide sequence where such changes donot substantially alter the overall biological activity of thepolypeptide.

Example of substitutions may be those, which are conservative (i.e.,wherein a residue is replaced by another of the same general type orgroup) or when wanted, non-conservative (i.e., wherein a residue isreplaced by an amino acid of another type). In addition, a non-naturallyoccurring amino acid may substitute for a naturally occurring amino acid(i.e., non-naturally occurring conservative amino acid substitution or anon-naturally occurring non-conservative amino acid substitution).

As is understood, naturally occurring amino acids may be sub-classifiedas acidic, basic, neutral and polar, or neutral and non-polar.Furthermore, three of the encoded amino acids are aromatic. It may be ofuse that encoded polypeptides differing from the determined polypeptideof the present invention contain substituted codons for amino acids,which are from the same type or group as that of the amino acid to bereplaced. Thus, in some cases, the basic amino acids Lys, Arg and Hismay be interchangeable; the acidic amino acids Asp and Glu may beinterchangeable; the neutral polar amino acids Ser, Thr, Cys, Gln, andAsn may be interchangeable; the non-polar aliphatic amino acids Gly,Ala, Val, Ile, and Leu are interchangeable but because of size Gly andAla are more closely related and Val, Ile and Leu are more closelyrelated to each other, and the aromatic amino acids Phe, Trp and Tyr maybe interchangeable.

It should be further noted that if the polypeptides are madesynthetically, substitutions by amino acids, which are not naturallyencoded by DNA (non-naturally occurring or unnatural amino acid) mayalso be made.

A non-naturally occurring amino acid is to be understood herein as anamino acid which is not naturally produced or found in a mammal. Anon-naturally occurring amino acid comprises a D-amino acid, an aminoacid having an acetylaminomethyl group attached to a sulfur atom of acysteine, a pegylated amino acid, etc. The inclusion of a non-naturallyoccurring amino acid in a defined polypeptide sequence will thereforegenerate a derivative of the original polypeptide. Non-naturallyoccurring amino acids (residues) include also the omega amino acids ofthe formula NH₂(CH₂)_(n)COOH wherein n is 2-6, neutral nonpolar aminoacids, such as sarcosine, t-butyl alanine, t-butyl glycine, N-methylisoleucine, norleucine, etc. Phenylglycine may substitute for Trp, Tyror Phe; citrulline and methionine sulfoxide are neutral nonpolar,cysteic acid is acidic, and ornithine is basic. Proline may besubstituted with hydroxyproline and retain the conformation conferringproperties.

It is known in the art that analogues may be generated by substitutionalmutagenesis and retain the biological activity of the polypeptides ofthe present invention. These analogues have at least one amino acidresidue in the protein molecule removed and a different residue insertedin its place. For example, one site of interest for substitutionalmutagenesis may include but are not restricted to sites identified asthe active site(s), or immunological site(s). Other sites of interestmay be those, for example, in which particular residues obtained fromvarious species are identical. These positions may be important forbiological activity. Examples of substitutions identified as“conservative substitutions” are shown in Table A. If such substitutionsresult in a change not desired, then other type of substitutions,denominated “exemplary substitutions” in Table A, or as furtherdescribed herein in reference to amino acid classes, are introduced andthe products screened.

In some cases it may be of interest to modify the biological activity ofa polypeptide by amino acid substitution, insertion, or deletion. Forexample, modification of a polypeptide may result in an increase in thepolypeptide's biological activity, may modulate its toxicity, may resultin changes in bioavailability or in stability, or may modulate itsimmunological activity or immunological identity. Substantialmodifications in function or immunological identity are accomplished byselecting substitutions that differ significantly in their effect onmaintaining (a) the structure of the polypeptide backbone in the area ofthe substitution, for example, as a sheet or helical conformation. (b)the charge or hydrophobicity of the molecule at the target site, or (c)the bulk of the side chain. Naturally occurring residues are dividedinto groups based on common side chain properties:

-   -   (1) hydrophobic: norleucine, methionine (Met), Alanine (Ala),        Valine (Val), Leucine (Leu), Isoleucine (Ile)    -   (2) neutral hydrophilic: Cysteine (Cys), Serine (Ser), Threonine        (Thr)    -   (3) acidic: Aspartic acid (Asp), Glutamic acid (Glu)    -   (4) basic: Asparagine (Asn), Glutamine (Gin), Histidine (His),        Lysine (Lys), Arginine (Arg)    -   (5) residues that influence chain orientation: Glycine (Gly),        Proline (Pro); and aromatic: Tryptophan (Trp), Tyrosine (Tyr),        Phenylalanine (Phe)

Non-conservative substitutions will entail exchanging a member of one ofthese classes for another.

TABLE A Examplary amino acid substitution Conservative Original residueExemplary substitution substitution Ala (A) Val, Leu, Ile Val Arg (R)Lys, Gln, Asn Lys Asn (N) Gln, His, Lys, Arg Gln Asp (D) Glu Glu Cys (C)Ser Ser Gln (Q) Asn Asn Glu (E) Asp Asp Gly (G) Pro Pro His (H) Asn,Gln, Lys, Arg Arg Ile (I) Leu, Val, Met, Ala, Phe, Leu norleucine Leu(L) Norleucine, Ile, Val, Met, Ile Ala, Phe Lys (K) Arg, Gln, Asn ArgMet (M) Leu, Phe, Ile Leu Phe (F) Leu, Val, Ile, Ala Leu Pro (P) Gly GlySer (S) Thr Thr Thr (T) Ser Ser Trp (W) Tyr Tyr Tyr (Y) Trp, Phe, Thr,Ser Phe Val (V) Ile, Leu, Met, Phe, Ala, Leu norleucine

It is to be understood herein, that if a “range” or “group” ofsubstances (e.g. amino acids), substituents” or the like is mentioned orif other types of a particular characteristic (e.g. temperature,pressure, chemical structure, time, etc.) is mentioned, the presentinvention relates to and explicitly incorporates herein each and everyspecific member and combination of sub-ranges or sub-groups thereinwhatsoever. Thus, any specified range or group is to be understood as ashorthand way of referring to each and every member of a range or groupindividually as well as each and every possible sub-ranges or sub-groupsencompassed therein; and similarly with respect to any sub-ranges orsub-groups therein. Thus, for example, with respect to a percentage (%)of identity of from about 80 to 100%, it is to be understood asspecifically incorporating herein each and every individual %, as wellas sub-range, such as for example 80%, 81%, 84.78%, 93%, 99% etc.; andsimilarly with respect to other parameters such as, concentrations,elements, etc.

It is in particular to be understood herein that the methods of thepresent invention each include each and every individual steps describedthereby as well as those defined as positively including particularsteps or excluding particular steps or a combination thereof; forexample an exclusionary definition for a method of the presentinvention, may read as follows: “provided that said polynucleotide doesnot comprise or consist in SEQ ID NO.:34 or the open reading frame ofSEQ ID NO.:34” or “provided that said polypeptide does not comprise orconsist in SEQ ID NO.:82” or “provided that said polynucleotide fragmentor said polypeptide fragment is less than X unit (e.g., nucleotides oramino acids) long or more than X unit (e.g., nucleotides or amino acids)long”.

Other objects, features, advantages, and aspects of the presentinvention will become apparent to those skilled in the art from thefollowing description. It should be understood, however, that thefollowing description and the specific examples, while indicatingpreferred embodiments of the invention, are given by way of illustrationonly. Various changes and modifications within the spirit and scope ofthe disclosed invention will become readily apparent to those skilled inthe art from reading the following description and from reading theother parts of the present disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

In the appended drawings:

For each of FIGS. 1 to 34 and 38-39 macroarrays were prepared using RAMPamplified RNA from human precursor cells (A-F 1), and differentiatedintermediate (A-F 2-3) and mature osteoclasts for four human donors (A-F4), and 30 different normal human tissues (adrenal (A5), liver (B5),lung (C5), ovary (D5), skeletal muscle (E5), heart (F5), cervix (G5),thyroid (H5), breast (A6), placenta (B6), adrenal cortex (C6), kidney(D6), vena cava (E6), fallopian tube (F6), pancreas (G6), testicle (H6),jejunum (A7), aorta (B7), esophagus (C7), prostate (D7), stomach (E7),spleen (F7), ileum (G7), trachea (A8), brain (B8), colon (C8), thymus(D8), small intestine (E8), bladder (F8) and duodenum (G8)). The STARdsDNA clone representing the respective SEQ ID NOs. was labeled with ³²Pand hybridized to the macroarray. The probe labeling reaction was alsospiked with a dsDNA sequence for Arabidopsis, which hybridizes to thesame sequence spotted on the macroarray (M) in order to serve as acontrol for the labeling reaction. Quantitation of the hybridizationsignal at each spot was performed using a STORM 820 phosphorimager andthe ImageQuant TL software (Amersham Biosciences, Piscataway, N.J.). Alog₂ value representing the average of the signals for the precursors(A-F 1) was used as the baseline and was subtracted from the log₂ valueobtained for each of the remaining samples in order to determine theirrelative abundancies compared to the precursors and plotted as a bargraph (right panel).

FIG. 1 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID.NO. 1. The hybridization results obtained confirms its upregulation inall of the human osteoclast samples with generally higher expression inthe more mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1)and little or no expression in all or most normal tissues (A-H 5-6 andA-G 7-8);

FIG. 2 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.2. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 3 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.3. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 4 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.4. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 5 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.5. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 6 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.6. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 7 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.7. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 8 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.8. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 9 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.9. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 10 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.10. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 11 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.11. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 12 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.12. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8.

FIG. 13 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.13. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 14 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.14. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 15 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.15. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 16 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.16. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 17 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.17. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8.

FIG. 18 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.18. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 19 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.19. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 20 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.20. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 21 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.21. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 22 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.22. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 23 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.23. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 24 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.24. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 25 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.25. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 26 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.26. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 27 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.27. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 28 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.28. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 29 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.29. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 30 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.30. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 31 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.31. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 32 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.32. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 33 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.33. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 34 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialexpression data for STAR selected osteoclast-specific human SEQ. ID. NO.34. The hybridization results obtained confirms its upregulation in allof the human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A-F 1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8);

FIG. 35 is a picture showing the knockdown effects on osteoclastogenesisby attenuating the endogenous expression of SEQ. ID. NO. 1 (AB0326) andSEQ. ID. NO. 2 (AB0369) using shRNA. A significant decrease in thenumber of multinucleated osteoclasts was observed from precursor cellsinfected with the AB0326 shRNA (FIG. 35A; bottom panel) and AB0369 shRNA(FIG. 1B; bottom panel) compared to those with the lacZ shRNA (FIGS. 35Aand B; top panels). These results clearly indicated that expression ofthe gene encoding SEQ. ID. NO. 1 (AB0326) and SEQ. ID. NO. 2 (AB0369)are required for osteoclast differentiation;

FIG. 36 is a picture showing the knockdown effects on osteoclastogenesisof the mouse orthologue for AB0326 (SEQ. ID. NO. 35) in the RAW 264.7model using shRNA-0326.2 (SEQ. ID. NO. 45). The RAW-0326.2 cell lineproduced significantly less osteoclasts (FIG. 36; bottom panel) comparedto the cell line containing the scrambled shRNA (FIG. 36; top panel).This result, coupled with that obtained in the human osteoclastprecursor cells using the lentiviral shRNA delivery system demonstratethat in both human and mouse, AB0326 gene product is clearly requiredfor osteoclastogenesis;

FIG. 37 is a picture showing the results of a functional complementationassay for SEQ. ID. NO. 1 (AB0326) in RAW-0326.2 cells to screen forinhibitors of osteoclastogenesis. The RAW-0326.2 cells transfected withthe empty pd2 vector are unable to form osteoclasts in the presence ofRANK ligand (center panel) indicating that the mouse AB0326 shRNA isstill capable of silencing the AB0326 gene expression in these cells.Conversely, the cells transfected with the cDNA for the human AB0326(pd2-hAB0326) are rescued and thus, differentiate more efficiently intoosteoclasts in response to RANK ligand (right panel). Wild-type RAW264.7 cells containing the empty vector (pd2) did not adversly affectthe formation of osteoclasts in the presence of RANK ligand (left panel)ruling out an effect due to pd2. Thus, this complementation assay can beused to screen for inhibitors of the human AB0326 polypeptide;

FIG. 38 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialExpression data for STAR selected osteoclast-specific human SEQ. ID. NO.85. Macroarrays were prepared using RAMP amplified RNA from humanprecursor cells (A-F 1), and differentiated intermediate and matureosteoclasts for four human donors (A-F 2-4), and 30 different normalhuman tissues (adrenal, liver, lung, ovary, skeletal muscle, heart,cervix, thyroid, breast, placenta, adrenal cortex, kidney, vena cava,fallopian tube, pancreas, testicle, jejunum, aorta, esophagus, prostate,stomach, spleen, ileum, trachea, brain, colon, thymus, small intestine,bladder and duodenum (A-H 5-6 and A-G 7-8)). The STAR clone representingSEQ. ID. NO. 85 was labeled with ³²P and hybridized to the macroarray.The hybridization results obtained confirms its upregulation in all ofthe human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A1-F1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8), and;

FIG. 39 is a picture of the macroarray hybridization results andquantitation of the signal intensities showing the differentialExpression data for STAR selected osteoclast-specific human SEQ. ID. NO.86. Macroarrays were prepared using RAMP amplified RNA from humanprecursor cells (A-F 1), and differentiated intermediate and matureosteoclasts for four human donors (A-F 2-4), and 30 different normalhuman tissues (adrenal, liver, lung, ovary, skeletal muscle, heart,cervix, thyroid, breast, placenta, adrenal cortex, kidney, vena cava,fallopian tube, pancreas, testicle, jejunum, aorta, esophagus, prostate,stomach, spleen, ileum, trachea, brain, colon, thymus, small intestine,bladder and duodenum (A-H 5-6 and A-G 7-8)). The STAR clone representingSEQ. ID. NO. 86 was labeled with ³²P and hybridized to the macroarray.The hybridization results obtained confirms its upregulation in all ofthe human osteoclast samples with generally higher expression in themore mature osteoclasts (A-F 2-4) compared to the precursors (A1-F1) andlittle or no expression in all or most normal tissues (A-H 5-6 and A-G7-8).

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The applicant employed a carefully planned strategy to identify andisolate genetic sequences involved in osteoclastogenesis and boneremodeling. The process involved the following steps: 1) preparation ofhighly representative cDNA libraries using mRNA isolated from precursorsand differentiated intermediate and mature osteoclasts of human origin;2) isolation of sequences upregulated during osteoclastogenesis; 3)identification and characterization of upregulated sequences; 4)selection of upregulated sequences for tissue specificity; and 5)determination of knock-down effects on osteoclastogenesis. The resultsdiscussed in this disclosure demonstrate the advantage of targetingosteoclast genes that are specific to this differentiated cell type andprovide a more efficient screening method when studying the geneticbasis of diseases and disorders. Genes that are known to have a role inother areas of biology have been shown to play a critical role inosteoclastogenesis and osteoclast function. Genes that are known buthave not had a role assigned to them until the present disclosure havealso been isolated and shown to have a critical role inosteoclastogenesis and osteoclast function. Finally, novel genes havebeen identified and play a role, however, applicant reserves theirdisclosure until further study has been completed.

The present invention is illustrated in further details below in anon-limiting fashion.

A—Material and Methods

Commercially available reagents referred to in the present disclosurewere used according to supplier's instructions unless otherwiseindicated. Throughout the present disclosure certain starting materialswere prepared as follows:

B—Preparation of Osteoclast Differentiated Cells

The RAW 264.7 (RAW) osteoclast precursor cell line and human precursorcells (peripheral blood mononuclear cells or CD34+ progenitors) are wellknown in the art as murine and human models of osteoclastogenesis. Thesemurine and human osteoclasts are therefore excellent sources ofmaterials for isolating and characterizing genes specialized forosteoclast function.

Human primary osteoclasts were differentiated from G-CSF-mobilizedperipheral blood mononuclear cells (Cambrex, East Rutherford, N.J.) asdescribed by the supplier in the presence of 35 ng/ml M-CSF and 100ng/ml RANK ligand. Multinucleated TRAP-staining osteoclasts were visibleby 11-14 days. Osteoclasts were also derived from human osteoclastsprecursor cells (CD34+ progenitors) (Cambrex, East Rutherford, N.J.) andcultured as described by the supplier. In the latter case, osteoclastswere obtained after 7 days.

RAW cells were purchased from American Type Culture Collection andmaintained in high glucose DMEM containing 10% fetal bovine serum andantibiotics. The cells were sub-cultured bi-weekly to a maximum of 10-12passages. For osteoclast differentiation experiments, RAW cells wereseeded in 96-well plates at a density of 4×10³ cells/well and allowed toplate for 24 h. Differentiation was induced in high glucose DMEM, 10%charcoal-treated foetal bovine serum (Hyclone, Logan, Utah), 0.05% BSA,antibiotics, 10 ng/ml macrophage colony stimulating factor (M-CSF), and100 ng/ml receptor activator of NF-kB (RANK) ligand. The plates werere-fed on day 3 and osteoclasts were clearly visible by day 4.Typically, the cells were stained for tartrate-resistant acidphosphatase (TRAP) on day 4 or 5 unless otherwise indicated. For TRAPstaining, the cells were washed with PBS and fixed in 10% formaldehydefor 1 h. After two PBS washes, the cells were rendered lightly permeablein 0.2% Triton X-100 in PBS for 5 min before washing in PBS. Stainingwas conducted at 37° C. for 20-25 min in 0.01% Naphtol AS-MX phosphate,0.06% Fast Red Violet, 50 mM sodium tartrate, 100 mM sodium acetate, pH5.2. Cells were visualized microscopically.

C—Method of Isolating Differentially Expressed mRNA

Key to the discovery of differentially expressed sequences unique toosteoclasts is the use of the applicant's patented STAR technology(Subtractive Transcription-based Amplification of mRNA; U.S. Pat. No.5,712,127 Malek et al., issued on Jan. 27, 1998). In this procedure,mRNA isolated from intermediate and mature osteoclasts is used toprepare “tester RNA”, which is hybridized to complementarysingle-stranded “driver DNA” prepared from osteoclast precursor mRNA andonly the un-hybridized “tester RNA” is recovered, and used to createcloned cDNA libraries, termed “subtracted libraries”. Thus, the“subtracted libraries” are enriched for differentially expressedsequences inclusive of rare and novel mRNAs often missed by micro-arrayhybridization analysis. These rare and novel mRNA are thought to berepresentative of important gene targets for the development of betterdiagnostic and therapeutic strategies.

The clones contained in the enriched “subtracted libraries” areidentified by DNA sequence analysis and their potential functionassessed by acquiring information available in public databases (NCBIand GeneCard). The non-redundant clones are then used to prepare DNAmicro-arrays, which are used to quantify their relative differentialexpression patterns by hybridization to fluorescent cDNA probes. Twoclasses of cDNA probes may be used, those which are generated fromeither RNA transcripts prepared from the same subtracted libraries(subtracted probes) or from mRNA isolated from different osteoclastsamples (standard probes). The use of subtracted probes providesincreased sensitivity for detecting the low abundance mRNA sequencesthat are preserved and enriched by STAR. Furthermore, the specificity ofthe differentially expressed sequences to osteoclast is measured byhybridizing radio-labeled probes prepared from each selected sequence tomacroarrays containing RNA from different osteoclast samples anddifferent normal human tissues. Additionally, Northern blot analysis isperformed so as to confirm the presence of one or more specific mRNAspecies in the osteoclast samples. Following this, the full-length cDNAsrepresentative of the mRNA species and/or spliced variants are cloned inE. coli DH10B.

A major challenge in gene expression profiling is the limited quantitiesof RNA available for molecular analysis. The amount of RNA isolated frommany osteoclast samples or human specimens (needle aspiration, lasercapture micro-dissection (LCM) samples and transfected cultured cells)is often insufficient for preparing: 1) conventional tester and drivermaterials for STAR; 2) standard cDNA probes for DNA micro-arrayanalysis; 3) RNA macroarrays for testing the specificity of expression;4) Northern blots and; 5) full-length cDNA clones for further biologicalvalidation and characterization etc. Thus, the applicant has developed aproprietary technology called RAMP (RNA Amplification Procedure) (U.S.patent application Ser. No. 11/000,958 published under No. US2005/0153333A1 on Jul. 14, 2005 and entitled “Selective Terminal Taggingof Nucleic Acids”), which linearly amplifies the mRNA contained in totalRNA samples yielding microgram quantities of amplified RNA sufficientfor the various analytical applications. The RAMP RNA produced islargely full-length mRNA-like sequences as a result of the proprietarymethod for adding a terminal sequence tag to the 3′-ends ofsingle-stranded cDNA molecules, for use in linear transcriptionamplification. Greater than 99.5% of the sequences amplified in RAMPreactions show <2-fold variability and thus, RAMP provides unbiased RNAsamples in quantities sufficient to enable the discovery of the uniquemRNA sequences involved in osteoclastogenesis.

D—Preparation of Human Osteoclasts Subtracted Library

Two human primary precursor cells from two different donors (Cambrex,East Rutherford, N.J.), and the corresponding intermediate (day 3 andday 7) and mature (days 11-14) osteoclasts were prepared as describedabove. Isolation of cellular RNA followed by mRNA purification from eachwas performed using standard methods (Qiagen, Mississauga, ON).Following the teachings of Malek et al. (U.S. Pat. No. 5,712,127), 2 μgof poly A+ mRNA from each sample were used to prepare highlyrepresentative (>2×10⁶ CFU) cDNA libraries in specialized plasmidvectors necessary for preparing tester and driver materials. In eachcase, first-strand cDNA was synthesized using an oligo dT₁₁ primer with3′ locking nucleotides (e.g., A, G or C) and containing a Not Irecognition site. Next, second-strand cDNA synthesis was performedaccording to the manufacturer's procedure for double-stranded cDNAsynthesis (Invitrogen, Burlington, ON) and the resulting double-strandedcDNA ligated to linkers containing an Asc I recognition site (NewEngland Biolabs, Pickering, ON). The double-stranded cDNAs were thendigested with Asc I and Not I restriction enzymes (New England Biolabs,Pickering, ON), purified from the excess linkers using the cDNAfractionation column from Invitrogen (Burlington, ON) as specified bythe manufacturer and each ligated into specialized plasmid vectors—p14(SEQ. ID. NO:36) and p17+ (SEQ. ID. NO:37) used for preparing tester anddriver materials respectively. Thereafter, the ligated cDNAs weretransformed into E. coli DH10B resulting in the desired cDNA libraries(RAW 264.7-precursor-p14, RAW 264.7-precursor-p17+, RAW264.7-osteoclasts-p14 and RAW 264.7-osteoclasts-p17+). The plasmid DNApool for each cDNA library was purified and a 2-μg aliquot of eachlinearized with Not I restriction enzyme. In vitro transcription of theNot I digested p14 and p17+ plasmid libraries was then performed with T7RNA polymerase and sp6 RNA polymerase respectively (Ambion, Austin,Tex.).

Next, in order to prepare 3′-represented tester and driver libraries, a10-μg aliquot of each of the in vitro synthesized RNA was converted todouble-stranded cDNA by performing first-strand cDNA synthesis asdescribed above followed by primer-directed (primer OGS 77 for p14 (SEQ.ID. NO:40) and primer OGS 302 for p17+ (SEQ. ID. NO:41)) second-strandDNA synthesis using Advantage-2 Taq polymerase (BD Biosciences Clontech,Mississauga, ON). The sequences corresponding to OGS 77 and OGS 302 wereintroduced into the in vitro synthesized RNA by way of the specializedvectors used for preparing the cDNA libraries. Thereafter, 6×1-μgaliquots of each double-stranded cDNA was digested individually with oneof the following 4-base recognition restriction enzymes Rsa I, Sau3A1,Mse I, Msp I, MinPI I and Bsh 12361 (MBI Fermentas, Burlington, ON),yielding up to six possible 3′-fragments for each RNA species containedin the cDNA library. Following digestion, the restriction enzymes wereinactivated with phenol and the set of six reactions pooled. Therestriction enzymes sites were then blunted with T4 DNA polymerase andligated to linkers containing an Asc I recognition site. Eachlinker-adapted pooled DNA sample was digested with Asc I and Not Irestriction enzymes, desalted and ligated to specialized plasmidvectors, p14 and p17 (p17 plasmid vector is similar to the p17+ plasmidvector except for the sequence corresponding to SEQ. ID. NO:41), andtransformed into E. coli DH10B. The plasmid DNA pool for each p14 andp17 3′-represented library was purified (Qiagen, Mississauga, ON) and a2-μg aliquot of each digested with Not I restriction enzyme, andtranscribed in vitro with either T7 RNA polymerase or sp6 RNA polymerase(Ambion, Austin, Tex.). The resulting p14 3′-represented RNA was useddirectly as “tester RNA” whereas, the p17 3′-represented RNA was used tosynthesize first-strand cDNA as described above, which then served as“driver DNA”. Each “driver DNA” reaction was treated with RNase A andRNase H to remove the RNA, phenol extracted and desalted before use.

The following 3′-represented libraries were prepared:

Tester 1 (donor 1-day 3)—human intermediate osteoclast-3′ in p14

Tester 2 (donor 1-day 7—human intermediate osteoclast)-3′ in p14

Tester 3 (donor 1-day 11—human mature osteoclast)-3′ in p14

Tester 4 (donor 2-day 3—human intermediate osteoclast)-3′ in p14

Tester 5 (donor 2-day 7—human intermediate osteoclast)-3′ in p14

Tester 6 (donor 2-day 13—human mature osteoclast)-3′ in p14

Driver 1 (donor 1-day 3)—human precursor-3′ in p17

Driver 2 (donor 2-day 3)—human precursor-3′ in p17

The tester RNA samples were subtracted following the teachings of U.S.Pat. No. 5,712,127 with the corresponding driver DNA in a ratio of 1:100for either 1- or 2-rounds following the teachings of Malek et al. (U.S.Pat. No. 5,712,127). Additionally, control reactions containing testerRNA and no driver DNA, and tester RNA plus driver DNA but no RNase Hwere prepared. The tester RNA remaining in each reaction aftersubtraction was converted to double-stranded DNA, and a volume of 5%removed and amplified in a standard PCR reaction for 30-cycles foranalytical purposes. The remaining 95% of only the driver plus RNase Hsubtracted samples were amplified for 4-cycles in PCR, digested with AscI and Not I restriction enzymes, and one half ligated into the pCATRMAN(SEQ. ID. NO:38) plasmid vector and the other half, into the p20 (SEQ.ID. NO:39) plasmid vector. The ligated materials were transformed intoE. coli DH10B and individual clones contained in the pCATRMAN librarieswere picked for further analysis (DNA sequencing and hybridization)whereas, clones contained in each p20 library were pooled for use assubtracted probes. Each 4-cycles amplified cloned subtracted librarycontained between 25,000 and 40,000 colonies.

The following cloned subtracted libraries were prepared:

-   SL90—tester 1 (day 3 osteoclast) minus driver 1 (precursor)    (1-round) in pCATRMAN;-   SL91—tester 2 (day 7 osteoclast) minus driver 1 (precursor)    (1-round) in pCATRMAN;-   SL92—tester 3 (day 11 osteoclast) minus driver 1 (precursor)    (1-round) in pCATRMAN;-   SL108—tester 1 (day 3 osteoclast) minus driver 1 (precursor)    (2-rounds) in pCATRMAN;-   SL109—tester 2 (day 7 osteoclast) minus driver 1 (precursor)    (2-rounds) in pCATRMAN;-   SL110—tester3 (day 11 osteoclast) minus driver 1 (precursor)    (2-rounds) in pCATRMAN;-   SL93—tester 4 (day 3 osteoclast) minus driver 2 (precursor)    (1-round) in pCATRMAN;-   SL94—tester 5 (day 7 osteoclast) minus driver 2 (precursor)    (1-round) in pCATRMAN;-   SL95—tester 6 (day 13 osteoclast) minus driver 2 (precursor)    (1-round) in pCATRMAN;-   SL87—tester 4 (day 3 osteoclast) minus driver 2 (precursor)    (2-rounds) in pCATRMAN;-   SL88—tester 5 (day 7 osteoclast) minus driver 2 (precursor)    (2-rounds) in pCATRMAN;-   SL89—tester 6 (day 11 osteoclast) minus driver 2 (precursor)    (2-rounds) in pCATRMAN

A 5-μL aliquot of the 30-cycles PCR amplified subtracted materialsdescribed above were visualized on a 1.5% agarose gel containingethidium bromide and then transferred to Hybond N⁺ (AmershamBiosciences, Piscataway, N.J.) nylon membrane for Southern blotanalysis. Using radiolabeled probes specific to the CTSK (cathepsin K;NM_(—)000396.2) gene, which is known to be upregulated in osteoclasts,and GAPDH (glyceraldehyde-3-phosphate dehydrogenase; M32599.1), which isa non-differentially expressed house-keeping gene, it was evident thatthere was subtraction of GAPDH but not CTSK. Based on these results, itwas anticipated that the subtracted libraries would be enriched fordifferentially expressed upregulated sequences.

E—Sequence Identification and Annotation of Clones Contained in theSubtracted Libraries:

A total of 6,912 individual colonies contained in the pCATRMANsubtracted libraries (SL87-95 and SL108-110) described above wererandomly picked using a Qbot (Genetix Inc., Boston, Mass.) into 60 μL ofautoclaved water. Then, 42 μL of each was used in a 100-μL standard PCRreaction containing oligonucleotide primers, OGS 1 and OGS 142 andamplified for 40-cycles (94° C. for 10 minutes, 40× (94° C. for 40seconds, 55° C. for 30 seconds and 72° C. for 2 minutes) followed by 72°C. for 7 minutes) in 96-wells microtitre plates using HotStart™ Taqpolymerase (Qiagen, Mississauga, ON). The completed PCR reactions weredesalted using the 96-well filter plates (Corning) and the ampliconsrecovered in 100 μL 10 mM Tris (pH 8.0). A 5-μL aliquot of each PCRreaction was visualized on a 1.5% agarose gel containing ethidiumbromide and only those reactions containing a single amplified productwere selected for DNA sequence analysis using standard DNA sequencingperformed on an ABI 3100 instrument (Applied Biosystems, Foster City,Calif.). Each DNA sequence obtained was given a Sequence IdentificationNumber and entered into a database for subsequent tracking andannotation.

Each sequence was selected for BLAST analysis of public databases (e.g.NCBI). Absent from these sequences were the standard housekeeping genes(GAPDH, actin, most ribosomal proteins etc.), which was a goodindication that the subtracted library was depleted of at least therelatively abundant non-differentially expressed sequences.

Once sequencing and annotation of the selected clones were completed,the next step involved identifying those sequences that were actuallyupregulated in osteoclasts compared to precursors.

F—Hybridization Analysis for Identifying Upregulated Sequences

The PCR amplicons representing the annotated sequences from the pCATRMANlibraries described above were used to prepare DNA microarrays. Thepurified PCR amplicons contained in 70 μL of the PCR reactions preparedin the previous section was lyophilized and each reconstituted in 20 μLof spotting solution comprising 3×SSC and 0.1% sarkosyl. DNAmicro-arrays of each amplicon in triplicate were then prepared usingCMT-GAP2 slides (Corning, Corning, N.Y.) and the GMS 417 spotter(Affymetrix, Santa Clara, Calif.).

The DNA micro-arrays were then hybridized with either standard orsubtracted cy3 and cy5 labelled cDNA probes as recommended by thesupplier (Amersham Biosciences, Piscataway, N.J.). The standard cDNAprobes were synthesized using RAMP amplified RNA prepared from thedifferent human osteoclast samples and the corresponding precursors. Itis well known to the skilled artisan that standard cDNA probes onlyprovide limited sensitivity of detection and consequently, low abundancesequences contained in the cDNA probes are usually missed. Thus, thehybridization analysis was also performed using cy3 and cy5 labelledsubtracted cDNA probes prepared from subtracted libraries representingthe different tester and driver materials. These subtracted librariesmay be enriched for low abundance sequences as a result of following theteachings of Malek et al., and therefore, may provide increaseddetection sensitivity.

All hybridization reactions were performed using the dye-swap procedureas recommended by the supplier (Amersham Biosciences, Piscataway, N.J.)and approximately 500 putatively differentially expressed upregulated(>2-fold) sequences were selected for further analysis.

G—Determining Osteoclast Specificity of the Differentially ExpressedSequences Identified:

The differentially expressed sequences identified in Section F for thedifferent human osteoclast subtracted libraries were tested forosteoclast specificity by hybridization to nylon membrane-basedmacroarrays. The macroarrays were prepared using RAMP amplified RNA fromhuman precursors and osteoclasts (intermediate and mature) of sixindependent experiments from 4 different donors (3 males and 1 female),and 30 normal human tissues (adrenal, liver, lung, ovary, skeletalmuscle, heart, cervix, thyroid, breast, placenta, adrenal cortex,kidney, vena cava, fallopian tube, pancreas, testicle, jejunum, aorta,esophagus, prostate, stomach, spleen, ileum, trachea, brain, colon,thymus, small intestine, bladder and duodenum) purchased commercially(Ambion, Austin, Tex.). Because of the limited quantities of mRNAavailable for many of these samples, it was necessary to first amplifythe mRNA using the RAMP methodology. Each amplified RNA sample wasreconstituted to a final concentration of 250 ng/μL in 3×SSC and 0.1%sarkosyl in a 96-well microtitre plate and 1 μL spotted onto Hybond N+nylon membranes using the specialized MULTI-PRINT™apparatus (VPScientific, San Diego, Calif.), air dried and UV-cross linked. A totalof 400 different sequences selected from SL87-95 and SL108-110 wereindividually radiolabeled with α-³²P-dCTP using the random primingprocedure recommended by the supplier (Amersham, Piscataway, N.J.) andused as probes on the macroarrays. Hybridization and washing steps wereperformed following standard procedures well known to those skilled inthe art.

Of the 500 sequences tested, approximately 85% were found to beupregulated in all of the osteoclast RNA samples that were used toprepare the macroarrays. However, many of these sequences were alsoreadily detected in a majority of the different normal human tissues.Based on these results, those sequences that appeared to be associatedwith experimental variability and those that were detected in many ofthe other human tissues at significantly elevated levels wereeliminated. Consequently, only 35 sequences, which appeared to beupregulated and highly osteoclast-specific, were selected for biologicalvalidation studies. Included in this set of 35 genes were 4 (SEQ. ID.NOs. 30-33) where there was a significant upregulation in matureosteoclasts compared to most normal tissues but because the expressionof these genes were overall lower in the precursor cells, they appearedto be elevated in the normal tissues after quantitation FIG. 30-33; bargraph). However, their expression in the normal tissues was stillrelatively lower than that of the mature osteoclasts. Thus, these genesmay still be important regulators in osteoclastogenesis and boneresorption and were therefore selected for biological validation. Thissubset of 35 sequences does not included genes also identified such as,CTSK, TRAP, MMP9, CST3 and CKB amongst others since these werepreviously reported in the literature to be upregulated in osteoclasts.The macroarray data for CST3 (SEQ. ID. NO. 34) is included to exemplifythe hybridization pattern and specificity of a gene that is alreadyknown to be a key regulator of the osteoclast resorption process. Onegene (ANKH; SEQ. ID. NO. 17) was included in the subset of 35 genesalthough it was previously reported in the database (NCBI-Gene) to playa role in bone mineralization. However, the observed bone phenotyperesulting from mutations in the ANKH gene was not specifically linked toits upregulation in osteoclasts. Thus our data suggests the importantrole for ANKH may be associated with osteoclast activity during boneremodeling.

FIGS. 1-33, 38 and 39 show the macroarray patterns and quantitation ofthe hybridization signals of the osteoclasts and normal human tissuesrelative to precursor cells for the 35 sequences selected for biologicalvalidation. Amongst the 35 selected sequences were 24 genes withfunctional annotation 9 genes with no functional annotation and 2 novelsequences (genomic hits). The identification of gene products involvedin regulating osteoclast differentiation and function has thus led tothe discovery of novel targets for the development of new and specifictherapies of disease states characterized by abnormal bone remodeling.Representative sequences summarized in Table 1 are presented below andcorresponding sequences are illustrated in Table 5.

SEQ. ID. NO:1:

SEQ. ID. NO:1 (Table 5) corresponds to a previously identified gene thatencodes a hypothetical protein, LOC284266 with an unknown function (seeTable 1). We have demonstrated that this gene is markedly upregulated inintermediate and mature osteoclast compared to precursor cells and othernormal human tissues (FIG. 1), which have not been previously reported.Thus, it is believed that this gene may be required forosteoclastogenesis and/or bone remodeling.

SEQ. ID. NO:2:

SEQ. ID. NO:2 (Table 5) corresponds to a previously identified gene thatencodes a predicted open reading frame, C6orf82 with an unknown function(see Table 1). We have demonstrated that this gene is markedlyupregulated in intermediate and mature osteoclast compared to precursorcells and other normal human tissues (FIG. 2), which have not beenpreviously reported. At least 5 transcript variants of this gene codingfor 3 protein isoforms has been identified so far (NCBI). Thus, it isbelieved that this gene may be required for osteoclastogenesis and/orbone remodeling.

SEQ. ID. NO:3:

SEQ. ID. NO:3 (Table 5) corresponds to a previously identified gene thatencodes a hypothetical protein, LOC133308 with an unknown function (seeTable 1) but may be involved in the process of pH regulation. We havedemonstrated that this gene is markedly upregulated in intermediate andmature osteoclast compared to precursor cells and other normal humantissues (FIG. 3), which have not been previously reported. Thus, it isbelieved that this gene may be required for osteoclastogenesis and/orbone remodeling.

SEQ. ID. NO:4:

SEQ. ID. NO:4 (Table 5) corresponds to a previously identified gene thatencodes a hypothetical protein, LOC116211 with an unknown function (seeTable 1). We have demonstrated that this gene is markedly upregulated inintermediate and mature osteoclast compared to precursor cells and othernormal human tissues (FIG. 4), which have not been previously reported.Thus, it is implified that this gene may be required forosteoclastogenesis and/or bone remodeling.

SEQ. ID. NO:5

SEQ. ID. NO:5 (Table 5) corresponds to a previously identified gene thatencodes a predicted protein, LOC151194 (similar to hepatocellularcarcinoma-associated antigen HCA557b), with unknown function (see Table1). We have demonstrated that this gene is markedly upregulated inintermediate and mature osteoclast compared to precursor cells and othernormal human tissues (FIG. 5), which have not been previously reported.Thus, it is believed that this gene may be required forosteoclastogenesis and/or bone remodeling.

SEQ. ID. NO:6:

SEQ. ID. NO:6 (Table 5) corresponds to a previously identified gene thatencodes a protein, chemokine (C-X-C motif) ligand 5 (CXCL5), which is aninflammatory chemokine that belongs to the CXC chemokine family (seeTable 1). We have demonstrated that this gene is significantlyupregulated in mature osteoclast compared to precursor cells and othernormal human tissues (FIG. 6), which have not been previously reported.Thus, it is believed that this gene may be required forosteoclastogenesis and/or bone remodeling.

SEQ. ID. NO:7:

SEQ. ID. NO:7 (Table 5) corresponds to a previously identified gene thatencodes a protein, ATPase, H+ transporting, lysosomal accessory protein2 (ATP6AP2), which is associated with adenosine triphosphatases(ATPases). Proton-translocating ATPases have fundamental roles in energyconservation, secondary active transport, acidification of intracellularcompartments, and cellular pH homeostasis (see Table 1). We havedemonstrated that this gene is markedly upregulated in mature osteoclastcompared to precursor cells and other normal human tissues (FIG. 7),which have not been previously reported. Thus, it is believed that thisgene may be required for osteoclastogenesis and/or bone remodeling.

SEQ. ID. NO:8

SEQ. ID. NO:8 (Table 5) corresponds to a previously identified gene thatencodes a protein, ubiquitin-specific protease 12-like 1 (USP12), whichis associated with ubiquitin-dependent protein catabolism (see Table 1).We have demonstrated that this gene is markedly upregulated inintermediate and mature osteoclast compared to precursor cells and othernormal human tissues (FIG. 8), which have not been previously reported.Thus, it is believed that this gene may be required forosteoclastogenesis and/or bone remodeling.

SEQ. ID. NO:9

SEQ. ID. NO:9 (Table 5) corresponds to a previously identified gene thatencodes a protein, Ubiquitin-conjugating enzyme E2E 1 (UBC4/5 homolog,yeast) (UBE2E1), which is associated with ubiquitin-dependent proteincatabolism (see Table 1). So far, there are 2 transcript variants andprotein isoforms reported for this gene. We have demonstrated that thisgene is significantly upregulated in mature osteoclast compared toprecursor cells and other normal human tissues (FIG. 9), which have notbeen previously reported. Thus, it is believed that this gene may berequired for osteoclastogenesis and/or bone remodeling.

SEQ. ID. NO:10

SEQ. ID. NO:10 (Table 5) corresponds to a previously identified genethat encodes a protein, Emopamil binding protein-like (EBPL), which mayhave cholestenol delta-isomerase activity (see Table 1). We havedemonstrated that this gene is markedly upregulated in intermediate andmature osteoclast compared to precursor cells and other normal humantissues (FIG. 10), which have not been previously reported. Thus, it isbelieved that this gene may be required for osteoclastogenesis and/orbone remodeling.

SEQ. ID. NO:11

SEQ. ID. NO:11 (Table 5) corresponds to a previously identified genethat encodes a protein, development and differentiation enhancing factor1 (DDEF1), which may be involved in cell motility and adhesion (seeTable 1). We have demonstrated that this gene is markedly upregulated inintermediate and mature osteoclast compared to precursor cells and othernormal human tissues (FIG. 11), which have not been previously reported.Thus, it is believed that this gene may be required forosteoclastogenesis and/or bone remodeling.

SEQ. ID. NO:12

SEQ. ID. NO:12 (Table 5) corresponds to a previously identified genethat encodes a protein, member 7 of the SLAM family (SLAM7), which mayhave receptor activity and involved in cell adhesion but still not fullycharacterized (see Table 1). We have demonstrated that this gene ismarkedly upregulated in mature osteoclast compared to precursor cellsand other normal human tissues (FIG. 12), which have not been previouslyreported. Thus, it is believed that this gene may be required forosteoclastogenesis and/or bone remodeling.

SEQ. ID. NO:13

SEQ. ID. NO:13 (Table 5) corresponds to a previously identified genethat encodes a protein, Ubiquitin-conjugating enzyme E2E 3 (UBC4/5homolog, yeast) (UBE2E3), which is associated with ubiquitin-dependentprotein catabolism (see Table 1). There are 2 transcript variantsdocumented so far, which code for the same protein isofrom. We havedemonstrated that this gene is markedly upregulated in mature osteoclastcompared to precursor cells and other normal human tissues (FIG. 1),which have not been previously reported. Thus, it is believed that thisgene may be required for osteoclastogenesis and/or bone remodeling.

SEQ. ID. NO:14

SEQ. ID. NO:14 (Table 5) corresponds to a previously identified genethat encodes a protein, Galanin (GAL), which is associated withneuropeptide hormone activity (see Table 1). We have demonstrated thatthis gene is markedly upregulated in intermediate and mature osteoclastcompared to precursor cells and other normal human tissues except forcolon (FIG. 14), which have not been previously reported. Thus, it isbelieved that this gene may be required for osteoclastogenesis and/orbone remodeling.

SEQ. ID. NO:15

SEQ. ID. NO:15 (Table 5) corresponds to a previously identified genethat encodes a protein, Cytokine-like nuclear factor n-pac (N-PAC),which may have oxireductase activity (see Table 1). We have demonstratedthat this gene is markedly upregulated in intermediate and matureosteoclast compared to precursor cells and other normal human tissues(FIG. 15), which have not been previously reported. However, someoverexpression of this gene but still way below that of matureosteoclasts were seen in heart, fallopian tube, spleen and cervix. Thus,it is believed that this gene may be required for osteoclastogenesisand/or bone remodeling.

SEQ. ID. NO:16

SEQ. ID. NO:16 (Table 5) corresponds to a previously identified genethat encodes a protein, Integrin alpha X (antigen CD11C (p150), alphapolypeptide) (ITGAX), which is involved in cell adhesion and ion binding(see Table 1). We have demonstrated that this gene is markedlyupregulated in intermediate and mature osteoclast compared to precursorcells and other normal human tissues (FIG. 16), which have not beenpreviously reported. Minimal expression but much lower than matureosteoclasts is observed for this gene in adrenal, lung and spleenamongst the normal tissues. Thus, it is believed that this gene may berequired for osteoclastogenesis and/or bone remodeling.

SEQ. ID. NO:17

SEQ. ID. NO:17 (Table 5) corresponds to a previously identified genethat encodes a protein, Ankylosis, progressive homolog (mouse) (ANKH),which is involved in regulating pyrophosphate levels, suggested as apossible mechanism regulating tissue calcification (see Table 1). Wehave demonstrated that this gene is markedly upregulated in intermediateand mature osteoclast compared to precursor cells and other normal humantissues (FIG. 17), which have not been previously reported. However,this gene has been reported to be involved in bone mineralization butwithout evidence of its upregulation in osteoclasts (Malkin et al.,2005). Thus, it is believed that this gene may be required forosteoclastogenesis and/or bone remodeling.

SEQ. ID. NO:18

SEQ. ID. NO:18 (Table 5) corresponds to a previously identified genethat encodes a protein, ATPase, H+ transporting, lysosomal 70 kD, V1subunit A, which is involved in hydrogen-transporting ATPase activity,rotational mechanism (see Table 1). We have demonstrated that this geneis markedly upregulated in mature osteoclast compared to precursor cellsand other normal human tissues (FIG. 18), which have not been previouslyreported. Thus, it is believed that this gene may be required forosteoclastogenesis and/or bone remodeling.

SEQ. ID. NO:19

SEQ. ID. NO:19 (Table 5) corresponds to a previously identified genethat encodes a predicted open reading frame coding for protein, FLJ10874(chromosome 1 open reading frame 75), which has no known function (seeTable 1). We have demonstrated that this gene is significantlyupregulated in mature osteoclast compared to precursor cells and othernormal human tissues (FIG. 19), which have not been previously reported.Thus, it is believed that this gene may be required forosteoclastogenesis and/or bone remodeling.

SEQ. ID. NO:20

SEQ. ID. NO:20 (Table 5) corresponds to a previously identified genethat encodes a protein, Integrin beta 1 binding protein 1 (ITGB1BP1),which has an important role during integrin-dependent cell adhesion (seeTable 1). Two transcript variants and protein isoforms for this gene hasbeen isolated. We have demonstrated that this gene is significantlyupregulated in mature osteoclast compared to precursor cells and othernormal human tissues (FIG. 20), which have not been previously reported.Thus, it is believed that this gene may be required forosteoclastogenesis and/or bone remodeling.

SEQ. ID. NO:21

SEQ. ID. NO:21 (Table 5) corresponds to a previously identified genethat encodes a protein, Thioredoxin-like 5 (TXNL5), which has no knownfunction (see Table 1). We have demonstrated that this gene issignificantly upregulated in intermediate and mature osteoclast comparedto precursor cells and other normal human tissues with the exception ofesophagus (FIG. 21), which have not been previously reported. Thus, itis believed that this gene may be required for osteoclastogenesis and/orbone remodeling.

SEQ. ID. NO:22

SEQ. ID. NO:22 (Table 5) corresponds to a previously identified genethat encodes a protein, C-type lectin domain family 4, member E(CLECSF9), which has no known specific function (see Table 1). Membersof this family share a common protein fold and have diverse functions,such as cell adhesion, cell-cell signaling, glycoprotein turnover, androles in inflammation and immune response. We have demonstrated thatthis gene is significantly upregulated in mature osteoclast compared toprecursor cells and other normal human tissues with the exception oflung and spleen (FIG. 22), which have not been previously reported. Atthis point, we cannot rule out cross hybridization to family members inlung and spleen. Thus, it is believed that this gene may be required forosteoclastogenesis and/or bone remodeling.

SEQ. ID. NO:23

SEQ. ID. NO:23 (Table 5) corresponds to a previously identified genethat encodes a protein, RAB33A, member RAS oncogene family (RAB33A),which has GTPase activity (see Table 1). We have demonstrated that thisgene is significantly upregulated in intermediate and mature osteoclastcompared to precursor cells and other normal human tissues with theexception of brain (FIG. 23), which have not been previously reported.Thus, it is believed that this gene may be required forosteoclastogenesis and/or bone remodeling.

SEQ. ID. NO:24

SEQ. ID. NO:24 (Table 5) corresponds to a previously identified genethat encodes a protein, Down syndrome critical region gene 1 (DSCR1),which interacts with calcineurin A and inhibits calcineurin-dependentsignaling pathways, possibly affecting central nervous systemdevelopment (see Table 1). There are 3 transcript variants and proteinisofroms isolated so far. We have demonstrated that this gene ismarkedly upregulated in intermediate and mature osteoclast compared toprecursor cells and other normal human tissues (FIG. 24), which have notbeen previously reported. Thus, it is believed that this gene may berequired for osteoclastogenesis and/or bone remodeling.

SEQ. ID. NO:25

SEQ. ID. NO:25 (Table 5) corresponds to a previously identified genethat encodes a protein, SNARE protein Ykt6 (YKT6), which is one of theSNARE recognition molecules implicated in vesicular transport betweensecretory compartments (see Table 1). We have demonstrated that thisgene is significantly upregulated in mature osteoclast compared toprecursor cells and other normal human tissues (FIG. 25), which have notbeen previously reported. Thus, it is believed that this gene may berequired for osteoclastogenesis and/or bone remodeling.

SEQ. ID. NO:26

SEQ. ID. NO:26 (Table 5) corresponds to a previously identified genethat encodes a protein, Actinin, alpha 1 (ACTN1), which is cytoskeletal,and involved in actin binding and adhesion (see Table 1). We havedemonstrated that this gene is significantly upregulated in intermediateand mature osteoclast compared to precursor cells and other normal humantissues (FIG. 26), which have not been previously reported. Thus, it isbelieved that this gene may be required for osteoclastogenesis and/orbone remodeling.

SEQ. ID. NO:27

SEQ. ID. NO:27 (Table 5) corresponds to a previously identified genethat encodes a protein, ClpX caseinolytic peptidase X homolog (E. coli)(CLPX), which may be involved in protein turnover (see Table 1). We havedemonstrated that this gene is significantly upregulated in intermediateand mature osteoclast compared to precursor cells and other normal humantissues (FIG. 27), which have not been previously reported. Thus, it isbelieved that this gene may be required for osteoclastogenesis and/orbone remodeling.

SEQ. ID. NO:28

SEQ. ID. NO:28 (Table 5) corresponds to a previously identified genethat encodes a protein, Carbonic anhydrase II (CA2), which has carbonatedehydratase activity (see Table 1). Defects in this enzyme areassociated with osteopetrosis and renal tubular acidosis (McMahon etal., 2001) and have been shown to be upregulated in mature osteoclastsunder induced acidic pH conditions (Biskobing and Fan, 2000). We havedemonstrated that this gene is markedly upregulated in intermediate andmature osteoclast compared to precursor cells independent of inducedacidic pH conditions and other normal human tissues (FIG. 28), whichhave not been previously reported. However, elevated expression of thisgene was also observed in colon and stomach but still significantlybelow the levels of mature osteoclasts. Thus, it is believed that thisgene may be required for osteoclastogenesis and/or bone remodeling.

SEQ. ID. NO:29

SEQ. ID. NO:29 (Table 5) corresponds to a previously identified genethat encodes a protein, Sorting nexin 10 (SNX10), whose function has notbeen determined (see Table 1). We have demonstrated that this gene ismarkedly upregulated in mature osteoclast compared to precursor cellsand most normal human tissues (FIG. 29), which have not been previouslyreported. However, elevated expression of this gene was also observed inliver, brain, lung, adrenal cortex, kidney and spleen but stillsignificantly below the levels of mature osteoclasts. Thus, it isbelieved that this gene may be required for osteoclastogenesis and/orbone remodeling.

SEQ. ID. NO:30

SEQ. ID. NO:30 (Table 5) corresponds to a previously identified genethat encodes a protein, Tudor domain containing 3 (TDRD3), whosefunction has not been determined but may be involved in nucleic acidbinding (see Table 1). We have demonstrated that this gene is markedlyupregulated in mature osteoclast compared to precursor cells and mostnormal human tissues (FIG. 30), which have not been previously reported.However, above baseline expression of this gene was observed in thenormal human tissues because of a lower than normal precursor level butit was still significantly below the levels of mature osteoclasts. Thus,this gene was still selected. Thus, it is believed that this gene may berequired for osteoclastogenesis and/or bone remodeling.

SEQ. ID. NO:31

SEQ. ID. NO:31 (Table 5) corresponds to a previously identified genethat encodes a protein, Selenoprotein P, plasma, 1 (SEPP1), which hasbeen implicated as an oxidant defense in the extracellular space and inthe transport of selenium (see Table 1). This gene encodes aselenoprotein that contains multiple selenocysteines. Selenocysteine isencoded by the usual stop codon UGA. The unususal amino acids areindicated as ‘U’ in the amino acid sequence in SEQ. ID. NO:78 (Table 5)or by Xaa in the sequence listing. We have demonstrated that this geneis markedly upregulated in intermediate and mature osteoclast comparedto precursor cells and most normal human tissues (FIG. 31), which havenot been previously reported. However, above baseline expression of thisgene was observed in the normal human tissues because of a lower thannormal precursor level but it was still significantly below the levelsof mature osteoclasts. Thus, this gene was still selected. Thus, it isbelieved that this gene may be required for osteoclastogenesis and/orbone remodeling.

SEQ. ID. NO:32

SEQ. ID. NO:32 (Table 5) corresponds to a previously identified genethat encodes a hypothetical protein, KIAA0040, which has no knownfunction (see Table 1). We have demonstrated that this gene is markedlyupregulated in intermediate and mature osteoclast compared to precursorcells and most normal human tissues (FIG. 32), which have not beenpreviously reported. However, above baseline expression of this gene wasobserved in the normal human tissues because of a lower than normalprecursor level but it was still significantly below the levels ofmature osteoclasts. Thus, this gene was still selected. Thus, it isbelieved that this gene may be required for osteoclastogenesis and/orbone remodeling.

SEQ. ID. NO:33

SEQ. ID. NO:33 (Table 5) corresponds to a previously identified genethat encodes a protein, Dipeptidylpeptidase 4 (CD26, adenosine deaminasecomplexing protein 2) (DPP4), which is an intrinsic membraneglycoprotein and a serine exopeptidase that cleaves X-proline dipeptidesfrom the N-terminus of polypeptides (see Table 1). We have demonstratedthat this gene is markedly upregulated in intermediate and matureosteoclast compared to precursor cells and most normal human tissues(FIG. 33), which have not been previously reported. However, abovebaseline expression of this gene was observed in the normal humantissues except for placenta, lung, ovary, kidney, prostate and smallintestine because of a lower than normal precursor level but it wasstill significantly below the levels of mature osteoclasts. Thus, thisgene was still selected. Thus, it is believed that this gene may berequired for osteoclastogenesis and/or bone remodeling.

SEQ. ID. NO:34:

SEQ. ID. NO:34 (Table 5) corresponds to a previously identified genethat encodes a protein, cystatin C precursor, with members of thecystatin family known to be inhibitor of cysteine proteases (see Table1). We have demonstrated that this gene is markedly upregulated inintermediate and mature osteoclast compared to precursor cells and othernormal human tissues (FIG. 34), which have not been previously reported.However, it is well documented that cystatin C plays a critical role ininhibiting bone resorption due to osteoclasts (Brage et al., 2005).Thus, the hybridization profile for this gene is an excellent example ofhighly upregulated and specific sequences related to osteoclasts.

SEQ. ID. NO:85

SEQ. ID. NO:85 (Table 5) encodes an unknown protein found on chromosome1 (clone RP11-344F13), which contains a novel gene (see Table 1). Wehave demonstrated that this gene is markedly upregulated in intermediateand mature osteoclast compared to precursor cells and other normal humantissues (FIG. 38), which have not been previously reported. Thus, it isimplified that this gene may be required for osteoclastogenesis and/orbone remodeling.

SEQ. ID. NO:86

SEQ. ID. NO:86 (Table 5) encodes no known protein. Unknown gene withmatching Est sequence in the data base corresponding to BQ182670isolated from an osteoarthritic cartilage sample (see Table 1). We havedemonstrated that this gene is significantly upregulated in intermediateand mature osteoclast compared to precursor cells and other normal humantissues (FIG. 39), which have not been previously reported. Thus, it isimplified that this gene may be required for osteoclastogenesis and/orbone remodeling.

H—Cloning of Full-Length cDNAs of Selected Sequences from OsteoclastmRNA:

It was necessary to obtain full-length cDNA sequences in order toperform functional studies of the expressed proteins. Spliced variantsare increasingly being implicated in tissue specific functions and assuch, it is important to work with cDNA clones from the system understudy. Applicant also recognizes that spliced variants may not always beinvolved. Thus, the applicant's approach has been to isolate therelevant full-length cDNA sequences directly from osteoclasts in orderto identify variants and their potential role with respect tospecificity.

Coding cDNA clones were isolated using both a 5′-RACE strategy(Invitrogen, Burlington, ON) and a standard two-primer gene specificapproach in PCR. The 5′-RACE strategy used cDNA prepared fromcap-selected osteoclast RNA and/or RAMP amplified osteoclast RNA. Foramplification using gene specific primers, either cDNA prepared fromRAMP RNA or total RNA was used. All cDNAs were synthesized followingstandard reverse transcription procedures (Invitrogen, Burlington, ON).The cDNA sequences obtained were cloned in E. coli DH10B and thenucleotide sequences for multiple clones determined. Thereafter, thecDNA sequences for each set were aligned and the open reading frame(s)(ORF) identified using standard software (e.g. ORF Finder-NCBI). Table 2shows the concensus sequence of the cDNA clones for the coding regionfor SEQ. ID. NO.1 (SEQ. ID. NO. 83) and SEQ. ID. NO.2 (SEQ. ID. NO. 84)obtained from a human osteoclast sample, which were identical to that ofthe published sequences corresponding to Accession# NM_(—)213602 andNM_(—)001014433 (NCBI), respectively.

I—RNA Interference Studies

RNA interference is a recently discovered gene regulation mechanism thatinvolves the sequence-specific decrease in a gene's expression bytargeting the mRNA for degradation and although originally described inplants, it has been discovered across many animal kingdoms fromprotozoans and invertebrates to higher eukaryotes (reviewed in Agrawalet al., 2003). In physiological settings, the mechanism of RNAinterference is triggered by the presence of double-stranded RNAmolecules that are cleaved by an RNAse III-like protein active in cells,called Dicer, which releases the 21-23 bp siRNAs. The siRNA, in ahomology-driven manner, complexes into a RNA-protein amalgamation termedRISC(RNA-induced silencing complex) in the presence of mRNA to causedegradation resulting in attenuation of that mRNA's expression (Agrawalet al., 2003).

Current approaches to studying the function of genes, such as geneknockout mice and dominant negatives, are often inefficient, andgenerally expensive, and time-consuming. RNA interference is proving tobe a method of choice for the analysis of a large number of genes in aquick and relatively inexpensive manner. Although transfection ofsynthetic siRNAs is an efficient method, the effects are often transientat best (Hannon G.J., 2002). Delivery of plasmids expressing shorthairpin RNAs by stable transfection has been successful in allowing forthe analysis of RNA interference in longer-term studies (Brummelkamp etal., 2002; Elbashir et al., 2001). In addition, more recent advanceshave permitted the expression of siRNA molecules, in the form of shorthairpin RNAs, in primary human cells using viral delivery methods suchas lentivirus (Lee et al., 2004; Rubinson et al., 2003).

J—Determination of Knockdown Effects on Osteoclastogenesis

In order to develop a screening method for the human candidate genes,RNA interference was adapted to deliver shRNAs into human osteoclastprecursor cells so that the expression of the candidate genes could beattenuated. This approach would then allow osteoclast differentiation tobe carried out in cells containing decreased expression of these genesto determine their requirement, if any, in this process.

To this end, a commercial lentiviral shRNA delivery system (Invitrogen,Burlington, ON) was utilized to introduce specific shRNAs into humanosteoclast precursor cells. The techniques used were as described by themanufacturer unless otherwise stated. In this example, the resultsobtained for two of the candidate genes, SEQ. ID. NO. 1 (AB0326) andSEQ. ID. NO. 2 (AB0369) tested so far, are presented. The proteinsencoded by both of these two genes have no known function. The shRNAsequences used to specifically target SEQ. ID. NO. 1 and SEQ. ID. NO. 2were 5′-CAGGCCCAGGAGTCCAATT-3′ (SEQ. ID. NO. 42) and5′-TCCCGTCTTTGGGTCAAAA-3′ (SEQ. ID. NO. 43) respectively. Briefly, atemplate for the expression of the shRNA was cloned into the lentiviralexpression vector and co-transfected in 293FT cells with expressionvectors for the viral structural proteins. After two days, supernatantscontaining the lentivirus were collected and stored at −80° C. Humanosteoclast precursors purchased from Cambrex (East Rutherford, N.J.)were seeded in 24-well plates and cultured in complete medium containingmacrophage-colony stimulating factor and allowed to adhere for threedays. After washing with PBS, the cells were infected with 20 MOIs(multiplicity of infection) of either lentiviral particles containing ashRNA specific for the bacterial lacZ gene as a control (lacZ shRNA) orSEQ. ID. NO. 1 (AB0326 shRNA) or SEQ. ID. NO. 2 (AB0369 shRNA). After 24h, the infected cells were treated with same medium containing 100 ng/mlRANK ligand for 5-8 days to allow for differentiation of osteoclast fromprecursor cells. Mature osteoclasts were fixed with formaldehyde andstained for TRAP expression as follows: the cells were washed with PBSand fixed in 10% formaldehyde for 1 h. After two PBS washes, the cellswere lightly permeabilized in 0.2% Triton X-100 in PBS for 5 min beforewashing in PBS. Staining was conducted at 37° C. for 20-25 min in 0.01%Naphtol AS-MX phosphate, 0.06% Fast Red Violet, 50 mM sodium tartrate,100 mM sodium acetate, pH 5.2. The stained cells were visualized bylight microscopy and photographed (magnification: 40×). A significantdecrease in the number of multinucleated osteoclasts was observed fromprecursor cells infected with the AB0326 shRNA (FIG. 35A; bottom panel)and AB0369 shRNA (FIG. 35B; bottom panel) compared to those with thelacZ shRNA (FIGS. 35A and B; top panels). Therefore, in both cases, therespective lentiviral shRNA (SEQ. ID. NOs. 42 and 43, respectively)(Table 4) perturbed osteoclastogenesis. These results clearly indicatedthat expression of the gene encoding SEQ. ID. NO. 1 (AB0326) and SEQ.ID. NO. 2 (AB0369) are required for osteoclast differentiation.

Similar experimentations to those described above are carried out forother sequences (SEQ ID NO.3 to SEQ ID NO.:33, SEQ ID NO.:85 or SEQ IDNO.:86).

K—Biological Validation of the Mouse Orthologue for AB0326 (SEQ. ID. NO.35) in Osteoclastogenesis Using the RAW 264.7 Model

As a means of developing a drug screening assay for the discovery oftherapeutic molecules capable of attenuating human osteoclastsdifferentation and activity using the targets identified, it wasnecessary to turn to another osteoclast differentiation model. The RAW264.7 (RAW) osteoclast precursor cell line is well known in the art as amurine model of osteoclastogenesis. However, due to the difficulty intransiently transfecting RAW cells, stable transfection was used as anapproach where shRNA are expressed in the RAW cells constitutively. Thispermitted long term studies such as osteoclast differentiation to becarried out in the presence of specific shRNAs specific to the mouseorthologues of the human targets identified.

RAW cells were purchased from American Type Culture Collection(Manassass, Va.) and maintained in high glucose DMEM containing 10%fetal bovine serum and antibiotics. The cells were sub-culturedbi-weekly to a maximum of 10-12 passages. For osteoclast differentiationexperiments, RAW cells were seeded in 96-well plates at a density of4×10³ cells/well and allowed to plate for 24 h. Differentiation wasinduced in high glucose DMEM, 10% charcoal-treated foetal bovine serum(obtained from Hyclone, Logan, Utah), 0.05% BSA, antibiotics, 10 ng/mlmacrophage colony stimulating factor (M-CSF), and 100 ng/ml RANK ligand.The plates were re-fed on day 3 and osteoclasts were clearly visible byday 4. Typically, the cells were stained for TRAP on day 4 or 5 unlessotherwise indicated.

To incorporate the shRNA-expression cassettes into the RAW cellchromosomes, the pSilencer 2.0 plasmid (SEQ. ID. NO. 47) was purchasedfrom Ambion (Austin, Tex.) and sequence-specific oligonucleotides wereligated as recommended by the manufacturer. Two shRNA expressionplasmids were designed and the sequences used for attenuating the mouseortholog of AB0326 (SEQ. ID. NO. 35) gene expression were5′-GCGCCGCGGATCGTCAACA-3′ (SEQ. ID. NO. 44) and5′-ACACGTGCACGGCGGCCAA-3′ (SEQ. ID. NO. 45). A plasmid supplied byAmbion containing a scrambled shRNA sequence with no known homology toany mammalian gene was also included as a negative control in theseexperiments. RAW cells were seeded in 6-well plates at a density of5×10⁵ cells/well and transfected with 1 μg of each plasmid using Fugene6(Roche, Laval, QC) as described in the protocol. After selection ofstable transfectants in medium containing 2 μg/ml puromycin, the celllines were expanded and tested in the presence of RANK ligand forosteoclastogenesis.

The stably transfected cell lines were designated RAW-0326.1, RAW-0326.2and RAW-ctl. In 96-well plates in triplicate, 4 000 cells/well wereseeded and treated with 100 ng/ml RANK ligand. After 4 days, osteoclastswere stained for TRAP expression and visualized by light microscopy(magnification was 40× and 100× as depicted in the left and rightpanels, respectively).

The representative results for the RAW-0326.2 line is shown in FIG. 36.The RAW-0326.2 cell line produced significantly less osteoclasts (FIG.36; bottom panel) compared to the cell line containing the scrambledshRNA (FIG. 36; top panel). The RAW-0326.1 cell line also showedattenuation of the mouse ortholog of AB0326 but not as pronounced (datanot shown). Therefore, as observed for SEQ ID NO.:42 and 43, siRNAs tothe mouse orthologue (SEQ. ID. NOs. 44 and 45) (Table 4) appear tophenotypically perturb osteoclast differentiation in the mouse model aswell. These results, coupled with that obtained in the human osteoclastprecursor cells using the lentiviral shRNA delivery system (section J),demonstrate that in both human and mouse, AB0326 gene product is clearlyrequired for osteoclastogenesis.

L—A Functional Complementation Assay for SEQ. ID. NO. 1 (AB0326) in RAW264.6 Cells to Screen for Inhibitors of Osteoclastogenesis

To establish a screening assay based on SEQ. ID. NO. 1 (AB0326) to findsmall molecules capable of attenuating osteoclast differentiation, thecDNA encoding human AB0326 was introduced into the RAW-0326.2 cell line.Thus, if the human AB0326 plays an identical functional role as themouse orthologue in RAW 264.7 cells, it should restore theosteoclastogenesis capabilities of the RAW-0326.2 cell line.

To accomplish this task, the RAW-0326.2 cell line was transfected withan eukaryotic expression vector encoding the full length cDNA for humanAB0326, termed pd2-hAB0326. This expression vector (pd2; SEQ. ID. NO.47) was modified from a commercial vector, pd2-EGFP-N1 (Clontech,Mountain View, Calif.) where the EGFP gene was replaced by the fulllength coding sequence of the human AB0326 cDNA. The AB0326 geneexpression was driven by a strong CMV promoter. Stable transfectantswere selected using the antibiotic, G418. This resulted in a RAW-0326.2cell line that expressed the human AB0326 gene product in which, themouse orthologue of AB0326 was silenced. As a control, RAW-0326.2 cellswere transfected with the pd2 empty vector, which should not complementthe AB0326 shRNA activity. Also, the pd2 empty vector was transfectedinto RAW 264.7 cells to serve as a further control. After selection ofstable pools of cells, 4 000 cells/well were seeded in 96-well platesand treated for 4 days with 100 ng/ml RANK ligand. Following fixationwith formaldehyde, the cells were stained for TRAP, anosteoclast-specific marker gene. As shown in FIG. 37, the RAW-0326.2cells transfected with the empty pd2 vector are still unable to formosteoclasts in the presence of RANK ligand (center panel) indicatingthat the mouse AB0326 shRNA is still capable of silencing the AB0326gene expression in these cells. Conversely, the cells transfected withhuman AB0326 (pd2-hAB0326) are rescued and thus, differentiate into moreosteoclasts in response to RANK ligand (right panel). RAW 264.7 cellscontaining the empty vector (pd2) did not adversly affect the formationof osteoclasts in the presence of RANK ligand (left panel). Theseresults confirm that the mouse and human orthologues of AB0326 arefunctionally conserved in osteoclast differentiation.

This particular type of cell-based assay can now serve as the basis forscreening compounds capable of binding to and inhibiting the function ofhuman AB0326. A compound library could be applied to this ‘rescued’ cellline in order to identify molecules (small molecule drugs, peptides, orantibodies) capable of inhibiting AB0326. Any reduction in osteoclastdifferentiation measured by a reduction in the expression of TRAP wouldbe indicative of a decrease in human AB0326 activity. This assay isapplicable to any gene required for proper osteoclast differentiation inRAW cells. A complementation assay can be developed for any human geneand used as the basis for drug screening.

Similar experimentation to those described above are carried out forother sequences (SEQ ID NO.3 to SEQ ID NO.:33 or SEQ ID NO.:85 or SEQ IDNO.:86). This type of assay may be used to screen for molecules capableof increasing or decreasing (e.g., inhibiting) the activity orexpression of NSEQ or PSEQ.

In the NSEQs of the present invention, their methods, compositions,uses, its, assays or else, the polynucleotide may either individually orin group (collectively) more particularly be (or may comprise or consistin) either;

a translatable portion of either SEQ ID NO.:1, of SEQ ID NO.:2, of SEQID NO.:3, of SEQ ID NO.:4, of SEQ ID NO.:5, of SEQ ID NO.:6, of SEQ IDNO.:7, of SEQ ID NO.:8, of SEQ ID NO.:9, of SEQ ID NO.:10, of SEQ IDNO.:11, of SEQ ID NO.:12, of SEQ ID NO.:13, of SEQ ID NO.:14, of SEQ IDNO.:15, of SEQ ID NO.:16, of SEQ ID NO.:17, of SEQ ID NO.:18, of SEQ IDNO.:19, of SEQ ID NO.:20, of SEQ ID NO.:21, of SEQ ID NO.:22, of SEQ IDNO.:23, of SEQ ID NO.:24, of SEQ ID NO.:25, of SEQ ID NO.:26, of SEQ IDNO.:27, of SEQ ID NO.:28, of SEQ ID NO.:29, of SEQ ID NO.:30, of SEQ IDNO.:31, of SEQ ID NO.:32, of SEQ ID NO.:33, of SEQ ID NO.:85 or of SEQID NO.:86;

sequence substantially identical to a translatable portion of SEQ IDNO.:1, of SEQ ID NO.:2, of SEQ ID NO.:3, of SEQ ID NO.:4, of SEQ IDNO.:5, of SEQ ID NO.:6, of SEQ ID NO.:7, of SEQ ID NO.:8, of SEQ IDNO.:9, of SEQ ID NO.:10, of SEQ ID NO.:11, of SEQ ID NO.:12, of SEQ IDNO.:13, of SEQ ID NO.:14, of SEQ ID NO.:15, of SEQ ID NO.:16, of SEQ IDNO.:17, of SEQ ID NO.:18, of SEQ ID NO.:19, of SEQ ID NO.:20, of SEQ IDNO.:21, of SEQ ID NO.:22, of SEQ ID NO.:23, of SEQ ID NO.:24, of SEQ IDNO.:25, of SEQ ID NO.:26, of SEQ ID NO.:27, of SEQ ID NO.:28, of SEQ IDNO.:29, of SEQ ID NO.:30, of SEQ ID NO.:31, of SEQ ID NO.:32, of SEQ IDNO.:33, of SEQ ID NO.:85 or of SEQ ID NO.:86;

a sequence substantially complementary to a translatable portion of SEQID NO.:1, a fragment of a transcribable portion of SEQ ID NO.:1, of SEQID NO.:2, of SEQ ID NO.:3, of SEQ ID NO.:4, of SEQ ID NO.:5, of SEQ IDNO.:6, of SEQ ID NO.:7, of SEQ ID NO.:8, of SEQ ID NO.:9, of SEQ IDNO.:10, of SEQ ID NO.:11, of SEQ ID NO.:12, of SEQ ID NO.:13, of SEQ IDNO.:14, of SEQ ID NO.:15, of SEQ ID NO.:16, of SEQ ID NO.:17, of SEQ IDNO.:18, of SEQ ID NO.:19, of SEQ ID NO.:20, of SEQ ID NO.:21, of SEQ IDNO.:22, of SEQ ID NO.:23, of SEQ ID NO.:24, of SEQ ID NO.:25, of SEQ IDNO.:26, of SEQ ID NO.:27, of SEQ ID NO.:28, of SEQ ID NO.:29, of SEQ IDNO.:30, of SEQ ID NO.:31, of SEQ ID NO.:32, of SEQ ID NO.:33, of SEQ IDNO.:85 or of SEQ ID NO.:86;

a fragment of a sequence substantially identical to a translatableportion of SEQ ID NO.:1, of SEQ ID NO.:2, of SEQ ID NO.:3, of SEQ IDNO.:4, of SEQ ID NO.:5, of SEQ ID NO.:6, of SEQ ID NO.:7, of SEQ IDNO.:8, of SEQ ID NO.:9, of SEQ ID NO.:10, of SEQ ID NO.:11, of SEQ IDNO.:12, of SEQ ID NO.:13, of SEQ ID NO.:14, of SEQ ID NO.:15, of SEQ IDNO.:16, of SEQ ID NO.:17, of SEQ ID NO.:18, of SEQ ID NO.:19, of SEQ IDNO.:20, of SEQ ID NO.:21, of SEQ ID NO.:22, of SEQ ID NO.:23, of SEQ IDNO.:24, of SEQ ID NO.:25, of SEQ ID NO.:26, of SEQ ID NO.:27, of SEQ IDNO.:28, of SEQ ID NO.:29, of SEQ ID NO.:30, of SEQ ID NO.:31, of SEQ IDNO.:32, of SEQ ID NO.:33, of SEQ ID NO.:85 or of SEQ ID NO.:86;

a fragment of a sequence substantially complementary to a translatableportion of SEQ ID NO.:1, of SEQ ID NO.:2, of SEQ ID NO.:3, of SEQ IDNO.:4, of SEQ ID NO.:5, of SEQ ID NO.:6, of SEQ ID NO.:7, of SEQ IDNO.:8, of SEQ ID NO.:9, of SEQ ID NO.:10, of SEQ ID NO.:11, of SEQ IDNO.:12, of SEQ ID NO.:13, of SEQ ID NO.:14, of SEQ ID NO.:15, of SEQ IDNO.:16, of SEQ ID NO.:17, of SEQ ID NO.:18, of SEQ ID NO.:19, of SEQ IDNO.:20, of SEQ ID NO.:21, of SEQ ID NO.:22, of SEQ ID NO.:23, of SEQ IDNO.:24, of SEQ ID NO.:25, of SEQ ID NO.:26, of SEQ ID NO.:27, of SEQ IDNO.:28, of SEQ ID NO.:29, of SEQ ID NO.:30, of SEQ ID NO.:31, of SEQ IDNO.:32, of SEQ ID NO.:33, of SEQ ID NO.:85 or of SEQ ID NO.:86;

or a library comprising any of the above.

In the PSEQs of the present invention, their methods, compositions,uses, kits assays, or else, the polypeptide may either individually orin group (collectively) more particularly be (or may comprise or consistin) either;

SEQ ID NO.:48, SEQ ID NO.:49, SEQ ID NO.:50, SEQ ID NO.:51, SEQ IDNO.:52, SEQ ID NO.:53, SEQ ID NO.:54, SEQ ID NO.:55, SEQ ID NO.:56, SEQID NO.:57, SEQ ID NO.:58, SEQ ID NO.:59, SEQ ID NO.:60, SEQ ID NO.:61,SEQ ID NO.:62, SEQ ID NO.:63, SEQ ID NO.:64, SEQ ID NO.:65, SEQ IDNO.:66, SEQ ID NO.:67, SEQ ID NO.:68, SEQ ID NO.:69, SEQ ID NO.:70, SEQID NO.:71, SEQ ID NO.:72, SEQ ID NO.:73, SEQ ID NO.:74, SEQ ID NO.:75SEQ ID NO.:76, SEQ ID NO.:77, SEQ ID NO.:78, SEQ ID NO.:79 or SEQ IDNO.:80;

a fragment of SEQ ID NO.:48, SEQ ID NO.:49, SEQ ID NO.:50, SEQ IDNO.:51, SEQ ID NO.:52, SEQ ID NO.:53, SEQ ID NO.:54, SEQ ID NO.:55, SEQID NO.:56, SEQ ID NO.:57, SEQ ID NO.:58, SEQ ID NO.:59, SEQ ID NO.:60,SEQ ID NO.:61, SEQ ID NO.:62, SEQ ID NO.:63, SEQ ID NO.:64, SEQ IDNO.:65, SEQ ID NO.:66, SEQ ID NO.:67, SEQ ID NO.:68, SEQ ID NO.:69, SEQID NO.:70, SEQ ID NO.:71, SEQ ID NO.:72, SEQ ID NO.:73, SEQ ID NO.:74,SEQ ID NO.:75 SEQ ID NO.:76, SEQ ID NO.:77, SEQ ID NO.:78, SEQ ID NO.:79or SEQ ID NO.:80;

or a biologically active analog, variant or a non-human hortologue ofSEQ ID NO.:48, SEQ ID NO.:49, SEQ ID NO.:50, SEQ ID NO.:51, SEQ IDNO.:52, SEQ ID NO.:53, SEQ ID NO.:54, SEQ ID NO.:55, SEQ ID NO.:56, SEQID NO.:57, SEQ ID NO.:58, SEQ ID NO.:59, SEQ ID NO.:60, SEQ ID NO.:61,SEQ ID NO.:62, SEQ ID NO.:63, SEQ ID NO.:64, SEQ ID NO.:65, SEQ IDNO.:66, SEQ ID NO.:67, SEQ ID NO.:68, SEQ ID NO.:69, SEQ ID NO.:70, SEQID NO.:71, SEQ ID NO.:72, SEQ ID NO.:73, SEQ ID NO.:74, SEQ ID NO.:75SEQ ID NO.:76, SEQ ID NO.:77, SEQ ID NO.:78, SEQ ID NO.:79 or SEQ IDNO.:80.

One of skill in the art will readily recognize that orthologues for allmammals maybe identified and verified using well-established techniquesin the art, and that this disclosure is in no way limited to one mammal.The term “mammal(s)” for purposes of this disclosure refers to anyanimal classified as a mammal, including humans, domestic and farmanimals, and zoo, sports, or pet animals, such as dogs, cats, cattle,horses, sheep, pigs, goats, rabbits, etc. Preferably, the mammal ishuman.

The sequences in the experiments discussed above are representative ofthe NSEQ being claimed and in no way limit the scope of the invention.The disclosure of the roles of the NSEQs in osteoclastogenesis andosteoclast function satisfies a need in the art to better understand thebone remodeling process, providing new compositions that are useful forthe diagnosis, prognosis, treatment, prevention and evaluation oftherapies for bone remodeling and associated disorders.

The art of genetic manipulation, molecular biology and pharmaceuticaltarget development have advanced considerably in the last two decades.It will be readily apparent to those skilled in the art that newlyidentified functions for genetic sequences and corresponding proteinsequences allows those sequences, variants and derivatives to be useddirectly or indirectly in real world applications for the development ofresearch tools, diagnostic tools, therapies and treatments for disordersor disease states in which the genetic sequences have been implicated.

Although the present invention has been described hereinabove by way ofpreferred embodiments thereof, it may be modified, without departingfrom the spirit and nature of the subject invention as defined in theappended claims.

TABLE 1 Differentially expressed sequences found in osteoclasts. NCBIORF Unigene Nucleotide Nucleotide #/Gene Positions/ Sequence Symbol/GeneAccession Polypeptide No. ID Number sequence No. Function SEQ ID NO. 1Hs.287692/ NM_213602 150-1136 hypothetical protein CD33L3/ encoding SEQLOC284266; 284266 ID NO.: 48 membrane associated function unknown SEQ IDNO. 2 Hs.520070/ NM_001014433 104-700 chromosome 6 open C6orf82/encoding SEQ reading frame 82; 51596 ID NO.: 49 membrane associated withunknown function SEQ ID NO. 3 Hs.546482/ NM_178833 633-2246 hypotheticalprotein LOC133308/ encoding SEQ LOC133308 possibly 133308 ID NO.: 50involved in regulation of pH SEQ ID NO. 4 Hs.135997/ NM_138461 112-741transmembrane 4 L LOC116211/ encoding SEQ six family member 19; 116211ID NO.: 51 function unknown SEQ ID NO. 5 Hs.558655/ NM_145280 172-82hypothetical protein LOC151194/ encoding SEQ LOC151194 151194 ID NO.: 52SEQ ID NO. 6 Hs.89714/ NM_002994 119-463 chemokine (C-X-C CXCL5/encoding SEQ motif) ligand 5 6374 ID NO.: 53 precursor; chemokineactivity SEQ ID NO. 7 Hs.495960/ NM_005765 103-1155 ATPase, H+ ATP6AP2/encoding SEQ transporting, 10159 ID NO.: 54 lysosomal accessory protein2; receptor activity SEQ ID NO. 8 Hs.42400/ NM_182488 259-1371ubiquitin-specific USP12/ encoding SEQ protease 12-like 1; 219333 IDNO.: 55 cysteine-type endopeptidase activity SEQ ID NO. 9 Hs.164853/NM_003341 175-756 ubiquitin-conjugating UBE2E1/ encoding SEQ enzyme E2E1 7324 ID NO.: 56 isoform 1; ligase activity SEQ ID NO. Hs.433278/NM_032565 53-673 emopamil binding 10 EBPL/ encoding SEQ related protein,84650 ID NO.: 57 delta8-delta7; integral to membrane SEQ ID NO.Hs.106015/ NM_018482 29-3418 development and 11 DDEF1/ encoding SEQdifferentiation 50807 ID NO.: 58 enhancing factor 1; membrane SEQ ID NO.Hs.517265/ NM_021181 16-1023 SLAM family member 12 SLAMF7/ encoding SEQ7; receptor activity 57823 ID NO.: 59 SEQ ID NO. Hs.470804/ NM_006357385-1008 ubiquitin-conjugating 13 UBE2E3/ encoding SEQ enzyme E2E 3;10477 ID NO.: 60 ligase activity SEQ ID NO. Hs.278959/ NM_015973 177-548galanin preproprotein; 14 GAL/ encoding SEQ neuropeptide 51083 ID NO.:61 hormone activity SEQ ID NO. NM_032569/ NM_032569 19-1680cytokine-like nuclear 15 N-PAC/ encoding SEQ factor n-pac; 3- 84656 IDNO.: 62 hydroxyisobutyrate dehydrogenase-like SEQ ID NO. Hs.248472/NM_000887 68-3559 integrin alpha X 16 ITGAX/ encodingSEQ precursor;cell-matrix 3687 ID NO.: 63 adhesion SEQ ID NO. Hs.156727/ NM_054027 321= 1799 ankylosis, progressive 17 ANKH/ encoding SEQ homolog; regulationof 1827 ID NO.: 64 bone mineralization SEQ ID NO. Hs.477155/ NM_00169067-1920 ATPase, H+ 18 ATP6V1A/ encoding SEQ transporting, 523 ID NO.: 65lysosomal 70 kD, V1 subunit A, isoform 1; proton transport; hydrolaseactivity SEQ ID NO. Hs.445386/ NM_018252 139-1191 hypothetical protein19 FLJ10874/ encoding SEQ LOC55248 55248 ID NO.: 66 SEQ ID NO.Hs.467662/ NM_004763 170-772 integrin cytoplasmic 20 ITGB1BP1/ encodingSEQ domain-associated 9270 ID NO.: 67 protein 1; cell adhesion SEQ IDNO. Hs.408236/ NM_032731 77-448 thioredoxin-like 5; 21 TXNL5/ encodingSEQ function unknown 84817 ID NO.: 68 SEQ ID NO. Hs.236516/ NM_014358152-811 C-type lectin, 22 CLECSF9/ encoding SEQ superfamily member 9;26253 ID NO.: 69 integral to membrane SEQ ID NO. Hs.56294/ NM_004794265-978 Ras-related protein 23 RAB33A/ encoding SEQ Rab-33A; small 9363ID NO.: 70 GTPase mediated signal transduction SEQ ID NO. Hs.282326/NM_004414 73-831 calcipressin 1 isoform 24 DSCR1/ encoding SEQ a;interacts with 1827 ID NO.: 71 calcineurin A and inhibits calcineurin-dependent signaling pathways SEQ ID NO. Hs.520794/ NM_006555 158-754SNARE protein Ykt6; 25 YKT6/ encoding SEQ vesicular transport 10652 IDNO.: 72 between secretory compartments SEQ ID NO. Hs.509765/ NM_001102184-2862 alpha-actinin 1; 26 ACTN1/ encoding SEQ structural constituent87 ID NO.: 73 of cytoskeleton; calcium ion binding SEQ ID NO. Hs.113823/NM_006660 73-1974 ClpX caseinolytic 27 CLPX/ encoding SEQ protease Xhomolog; 10845 ID NO.: 74 energy-dependent regulator of proteolysis SEQID NO. Hs.155097/ NM_000067 66-848 carbonic anhydrase II; 28 CA2/encoding SEQ carbonate 760 ID NO.: 75 dehydratase activity SEQ ID NO.Hs.520714/ NM_013322 216-821 sorting nexin 10; 29 SNX10/ encoding SEQfunction unknown 29887 ID NO.: 76 SEQ ID NO. Hs.525061/ NM_030794258-2213 tudor domain 30 TDRD3/ encoding SEQ containing 3; nucleic 81550ID NO.: 77 acid binding SEQ ID NO. Hs.275775/ NM_005410 101-1246selenoprotein P; 31 SEPP1/ encoding SEQ extracellular space 6414 ID NO.:78 implicated in defense SEQ ID NO. Hs.518138/ NM_014656 921-1382KIAA0040; novel 32 KIAA0040/ encoding SEQ protein 9674 ID NO.: 79 SEQ IDNO. Hs.368912/ NM_001935 562-2862 dipeptidylpeptidase 33 DPP4/ encodingSEQ IV; aminopeptidase 1803 ID NO.: 80 activity SEQ ID NO. Hs.304682/NM_000099 76-516 cysteine protease 34 CST3/ encoding SEQ inhibitoractivity 1471 ID NO.: 81 SEQ ID NO. None/ AL357873 Novel novel 85 none/none SEQ ID NO. AL645465/ novel novel 86 BQ182670

TABLE 2 Shows the concensus sequences for SEQ. ID. NO. 1 and SEQ. ID.NO. 2 cloned from a mature human osteoclast sample. ORF SequenceNucleotide Polypeptide Identification Positions sequence No. SEQ ID NO.83 1-987 SEQ ID NO. 48 SEQ ID NO. 84 1-471 SEQ ID NO. 49

TABLE 3 List of mouse orthologue for AB0326 NCBI ORF PolypeptideSequence Unigene Accession Nucleotide sequence Identification ClusterNumber Positions No. SEQ ID None/ XM_884636 122-1102/ SEQ ID NO. 35LOC620235/ similar to NO.: 82 620235 neural cell adhesion molecule2/unknown function

TABLE 4 list of additional sequences identification of plasmids andshRNA oligonucleotides Sequence Identification name Description SEQ. ID.NO. 36 p14 Vector for STAR SEQ. ID. NO. 37 p17+ Vector for STAR SEQ. ID.NO. 38 pCATRMAN Vector for STAR SEQ. ID. NO. 39 p20 Vector for STAR SEQ.ID. NO. 40 OGS 77 Primer used for STAR p14 vector SEQ. ID. NO. 41 OGS302 Primer used for STAR p17+ vector SEQ. ID. NO: 42 human 0326.1 siRNAsequence for SEQ. ID. NO. 1 SEQ. ID. NO: 43 Human 0369.1 shRNA sequencefor SEQ. ID. NO. 2 SEQ. ID. NO: 44 mouse 0326.1 shRNA sequence for SEQ.ID. NO. 35 SEQ. ID. NO: 45 mouse 0326.2 shRNA sequence for SEQ ID NO. 35SEQ. ID. NO: 46 pSilencer2.0 vector SEQ. ID. NO: 47 pd2 vector

TABLE 5 Nucleotide Sequence (5′-3′) ORFs SEQ ID NO.: 1 SEQ ID NO.: 48TCCGGCTCCCGCAGAGCCCACAGGGACCTGCAGATCTGAGTGCCCTGCCCACCCCCGCCCGCCTTCCTTCCCCCACCACGCCTGGGAMEKSIWLLACLAWVGGGCCCTCACTGGGGAGGTGGCCGAGAACGGGTCTGGCCTGGGGTGTTCAGATGCTCACAGCATGGAAAAGTCCATCTGGCTGCTGGLPTGSFVRTKIDTTCCTGCTTGGCGTGGGTTCTCCCGACAGGCTCATTTGTGAGAACTAAAATAGATACTACGGAGAACTTGCTCAACACAGAGGTGCACAENLLNTEVHSSPAQGCTCGCCAGCGCAGCGCTGGTCCATGCAGGTGCCACCCGAGGTGAGCGCGGAGGCAGGCGACGCGGCAGTGCTGCCCTGCACCTTCARWSMQVPPEVSAEACGCACCCGCACCGCCACTACGACGGGCCGCTGACGGCCATCTGGCGCGCGGGCGAGCCCTATGCGGGCCCGCAGGTGTTCCGCTGCGGDAAVLPCTFTHPHCTGCGGCGCGGGGCAGCGAGCTCTGCCAGACGGCGCTGAGCCTGCACGGCCGCTTCCGGCTGCTGGGCAACCCGCGCCGCAACGACCRHYDGPLTAIWRAGTCTCGCTGCGCGTCGAGCGCCTCGCCCTGGCTGACGACCGCCGCTACTTCTGCCGCGTCGAGTTCGCCGGCGACGTCCATGACCGCTEPYAGPQVFRCAAAACGAGAGCCGCCACGGCGTCCGGCTGCACGTGACAGCCGCGCCGCGGATCGTCAACATCTCGGTGCTGCCCAGTCCGGCTCACGCCTRGSELCQTALSLHGTCCGCGCGCTCTGCACTGCCGAAGGGGAGCCGCCGCCCGCCCTCGCCTGGTCCGGCCCGGCCCTGGGCAACAGCTTGGCAGCCGTGCRFRLLGNPRRNDLSGGAGCCCGCGTGAGGGTCACGGCCACCTAGTGACCGCCGAACTGCCCGCACTGACCCATGACGGCCGCTACACGTGTACGGCCGCCALRVERLALADDRRYACAGCCTGGGCCGCTCCGAGGCCAGCGTCTACCTGTTCCGCTTCCATGGCGCCAGCGGGGCCTCGACGGTCGCCCTCCTGCTCGGCGFCRVEFAGDVHDRYCTCTCGGCTTCAAGGCGCTGCTGCTGCTCGGGGTCCTGGCCGCCCGCGCTGCCCGCCGCCGCCCAGAGCATCTGGACACCCCGGACAESRHGVRLHVTAAPCCCCACCACGGTCCCAGGCCCAGGAGTCCAATTATGAAAATTTGAGCCAGATGAACCCCCGGAGCCCACCAGCCACCATGTGCTCACRIVNISVLPSPAHACGTGAGGAGTCCCTCAGCCACCAACATCCATTTCAGCACTGTAAAGAACAAAGGCCAGTGCGAGGCTTGGCTGGCACAGCCAGTCCTFRALCTAEGEPPPAGGTTCTCGGGCACCTTGGCAGCCCCCAGCTGGGTGGCTCCTCCCCTGCTCAAGGTCAAGACCCTGCTCAAGGAGGCTCATCTGGCCTLAWSGPALGNSLAACCTATGTGGACAACCATTTCGGAGCTCCCTGATATTTTTGCCAGCATTTCGTAAATGTGCATACGTCTGTGTGTGTGTGTGTGTGTGVRSPREGHGHLVTAAGAGAGAGAGAGAGAGAGTACACGCATTAGCTTGAGCGTGAAACTTCCAGAAATGTTCCCTTGCCCTTTCTTACCTAGAACACCTGCELPALTHDGRYTCT TATAGTAAAGCAGACAGGAAACTGTTAAAAAAAAAAAAAAAAAAAANSLGRSEASVYL FRFHGASGASTVAL LLGALGFKALLLLG VLAARAARRRPEHLDTPDTPPRSQAQES NYENLSQMNPRSPP ATMCSP SEQ ID NO.: 2 SEQ ID NO.: 49ACGGAAACGGGCGTGCCATTTCCGCGCACGTCTGCAGATGCGGTAGTCGATTGGTCAAGTCTCCCATGGCTCCTCCTTCATCAGGAGMIGSGLAGSGGAGGGTGGGCAAACCGCGCCATGATAGGGTCGGGATTGGCTGGCTCTGGAGGCGCAGGTGGTCCTTCTTCTACTGTCACATGGTGCGCGCTPSSTVTWCALFSNHGTTTTCTAATCACGTGGCTGCCACCCAGGCCTCTCTGCTCCTGTCTTTTGTTTGGATGCCGGCGCTGCTGCCTGTGGCCTCCCGCCTVAATQASLLLSFVWTTTGTTGCTACCCCGAGTCTTGCTGACCATGGCCTCTGGAAGCCCTCCGACCCAGCCCTCGCCGGCCTCGGATTCCGGCTCTGGCTAMPALLPVASRLLLLCGTTCCGGGCTCGGTCTCTGCAGCCTTTGTTACTTGCCCCAACGAGAAGGTCGCCAAGGAGATCGCCAGGGCCGTGGTGGAGAAGCGPRVLLTMASGSPPTCCTAGCAGCCTGCGTCAACCTCATCCCTCAGATTACATCCATCTATGAGTGGAAAGGGAAGATCGAGGAAGACAGTGAGGTGCTGATQPSPASDSGSGYVPGATGATTAAAACCCAAAGTTCCTTGGTCCCAGCTTTGACAGATTTTGTTCGTTCTGTGCACCCTTACGAAGTGGCCGAGGTAATTGCGSVSAAFVTCPNEKATTGCCTGTGGAACAGGGGAACTTTCCGTACCTGCAGTGGGTGCGCCAGGTCACAGAGTCAGTTTCTGACTCTATCACAGTCCTGCCVAKEIARAVVEKRLATGATGAGCCCTGTTCCTGCTCATCATGAAGATCCCCGCGATACTTCAACGCCTTCTGACTTCCAGGTGATGACTGGGCCCCCAATAAACVNLIPQITSIY AATCCCGTCTTTGGGTCTCTCTGCCAAAAAAAAAAAAAAA EWKGKIEEDSEVLMMIKTQSSLVPALTD FVRSVHPYEVAEVI ALPVEQGNFPYLQW VRQVTESVSDSITV LP SEQ IDNO.: 3 SEQ ID NO.: 50CGGTGTCTCGTCATCTCCGGGAAGACTCGGCGCCTGGGTCCGCGCTCTCTGGGTAAGCTTTCCGGGAAGCTTTCCCGGGAGCTCGCTMGDEDKRITYEDSEGGTCCTGGCCCCAGAAGCCTGCGGACCCGCCCAGGGAGGATAAGCAGCTGAAAGACCGCGCGGTGCCGCTCCGAGGCCCCGGGACGTPSTGMNYTPSMHQEGGGCCCATGGTCGGCCTGGCGCCACCTTTCCGGGGGAAGCCACGCGCACCAGGCATCGCACGCGGCTCTGCACCCGCGCCGCCGGACAQEETVMKLKGIDACTGAAACCCGGCGGAGGGCACACGGGGCTGCCGCTGCGGGCCCCGGACCAACCCATGCTTACTCCGGAGCCTGTACCGGCGCCGACGNEPTEGSILLKSSEGGTCGGACCTCCCTGCGCGGTGTCGCCCAGCGGGTTCGTGCGAAAGGCGGGGCCGACTACACGCGGTGCCGCGCCCTGAGACCGTTTKKLQETPTEANHVQATCTGCAGTCAACGCAGCCTCCCGGCTCAGCCTGGGAAGATGCGCGAATCGGGAACCCCAGAGCGCGGTGGCTAGACCGGGCTCCGCRLRQMLACPPHGLLCGCCTCCCCCACAGCCCCTTTCCTAATCGTTCAGACGGAGCCTGGTCGACTTCGCCGGAGACTGCCAGATCTCGTTCCTCTTCCCTGDRVITNVTIIVLLWTGTCATCTTCTTAATTATAAATAATGGGGGATGAAGATAAAAGAATTACATATGAAGATTCAGAACCATCCACAGGAATGAATTACAAVVWSITGSECLPGCGCCCTCCATGCATCAAGAAGCACAGGAGGAGACAGTTATGAAGCTCAAAGGTATAGATGCAAATGAACCAACAGAAGGAAGTATTCGNLFGIIILFYCAITTTTGAAAAGCAGTGAAAAAAAGCTACAAGAAACACCAACTGAAGCAAATCACGTACAAAGACTGAGACAAATGCTGGCTTGCCCTCIGGKLLGLIKLPTLCACATGGTTTACTGGACAGGGTCATAACAAATGTTACCATCATTGTTCTTCTGTGGGCTGTAGTTTGGTCAATTACTGGCAGTGAATPPLPSLLGMLLAGFGTCTTCCTGGAGGAAACCTATTTGGAATTATAATCCTATTCTATTGTGCCATCATTGGTGGTAAACTTTTGGGGCTTATTAAGTTACLIRNIPVINDNVQICTACATTGCCTCCACTGCCTTCTCTTCTTGGCATGCTGCTTGCAGGGTTTCTCATCAGAAATATCCCAGTCATCAACGATAATGTGCKHKWSSSLRSIALSAGATCAAGCACAAGTGGTCTTCCTCTTTGAGAAGCATAGCCCTGTCTATCATTCTGGTTCGTGCTGGCCTTGGTCTGGATTCAAAGGIILVRAGLGLDSKACCCTGAAGAAGTTAAAGGGCGTTTGTGTAAGACTGTCCATGGGTCCCTGTATTGTGGAGGCGTGCACATCTGCTCTTCTTGCCCATTLKKLKGVCVRLSMGACCTGCTGGGTTTACCATGGCAATGGGGATTTATACTGGGTTTTGTTTTAGGTGCTGTATCTCCAGCTGTTGTGGTGCCTTCAATGCPCIVEACTSALLAHTCCTTTTGCAGGGAGGAGGCTATGGTGTTGAGAAGGGTGTCCCAACCTTGCTCATGGCAGCTGGCAGCTTCGATGACATTCTGGCCAYLLGLPWQWGFILGTCACTGGCTTCAACACATGCTTGGGCATAGCCTTTTCCACAGGCTCTACTGTCTTTAATGTCCTCAGAGGAGTTTTGGAGGTGGTAAFVLGAVSPAVVVPSTTGGTGTGGCAACTGGATCTGTTCTTGGATTTTTCATTCAGTACTTTCCAAGCCGTGACCAGGACAAACTTGTGTGTAAGAGAACATMLLLQGGGYGVEKGTCCTTGTGTTGGGGTTGTCTGTGCTAGCTGTGTTCAGCAGTGTGCATTTTGGTTTCCCTGGATCAGGAGGACTGTGCACGTTGGTCAVPTLLMAAGSFDDITGGCTTTCCTTGCAGGCATGGGATGGACCAGCGAAAAGGCAGAGGTTGAAAAGATAATTGCAGTTGCCTGGGACATTTTTCAGCCCCLAITGFNTCLGIAFTTCTTTTTGGACTAATTGGAGCAGAGGTATCTATTGCATCTCTCAGACCAGAAACTGTAGGCCTTTGTGTTGCCACCGTAGGCATTGSTGSTVFNVLRGVLCAGTATTGATACGAATTTTGACTACATTTCTGATGGTGTGTTTTGCTGGTTTTAACTTAAAAGAAAAGATATTTATTTCTTTTGCATEVVIGVATGSVLGFGGCTTCCAAAGGCCACAGTTCAGGCTGCAATAGGATCTGTGGCTTTGGACACAGCAAGGTCACATGGAGAGAAACAATTAGAGGACTFIQYFPSRDQDKLVATGGAATGGATGTGTTGACAGTGGCATTTTTGTCCATCCTCATCACAGCCCCAATTGGAAGTCTGCTTATTGGTTTACTGGGCCCCACKRTFLVLGLSVLAGGCTTCTGCAGAAAGTTGAACATCAAAATAAAGATGAAGAAGTTCAAGGAGAGACTTCTGTGCAAGTTTAGAGGTGAAAAGAGAGAGVFSSVHFGFPGSGGTGCTGAACATAATGTTTAGAAAGCTGCTACTTTTTTCAAGATGCATATTGAAATATGTAATGTTTAAGCTTAAAATGTAATAGAACCLCTLVMAFLAGMGWAAAAGTGTAGCTGTTTCTTTAAACAGCATTTTTAGCCCTTGCTCTTTCCATGTGGGTGGTAATGATTCTATATCCCCAAAAAAAAAATSEKAEVEKIIAVA AAAAAAAAAAA WDIFQPLLFGLIGA EVSIASLRPETVGL CVATVGIAVLIRILTTFLMVCFAGFNLK EKIFISFAWLPKAT VQAAIGSVALDTAR SHGEKQLEDYGMDVLTVAFLSILITAPI GSLLIGLLGPRLLQ KVEHQNKDEEVQGE TSVQV SEQ ID NO.: 4 SEQ IDNO.: 51GACAACCTTCAGGTCCAGCCCTGGAGCTGGAGGAGTGGAGCCCCACTCTGAAGACGCAGCCTTTCTCCAGGTTCTGTCTCTCCCATTMVSSPCTPASSRTCCTGATTCTTGACACCAGATGCAGGATGGTGTCCTCTCCCTGCACGCCGGCAAGCTCACGGACTTGCTCCCGTATCCTGGGACTGAGCSRILGLSLGTAALFCTTGGGACTGCAGCCCTGTTTGCTGCTGGGGCCAACGTGGCACTCCTCCTTCCTAACTGGGATGTCACCTACCTGTTGAGGGGCCTCAAGANVALLLPNWDCTTGGCAGGCATGCCATGCTGGGAACTGGGCTCTGGGGAGGAGGCCTCATGGTACTCACTGCAGCTATCCTCATCTCCTTGATGGGCVTYLLRGLLGRHAMTGGAGATACGGCTGCTTCAGTAAGAGTGGGCTCTGTCGAAGCGTGCTTACTGCTCTGTTGTCAGGTGGCCTGGCTTTACTTGGAGCCLGTGLWGGGLMVLTCTGATTTGCTTTGTCACTTCTGGAGTTGCTCTGAAAGATGGTCCTTTTTGCATGTTTGATGTTTCATCCTTCAATCAGACACAAGCTAAILISLMGWRYGCTGGAAATATGGTTACCCATTCAAAGACCTGCATAGTAGGAATTATCTGTATGACCGTTCGCTCTGGAACTCCGTCTGCCTGGAGCCCFSKSGLCRSVLTALTCTGCAGCTGTTGTCTGGCACGTGTCCCTCTTCTCCGCCCTTCTGTGCATCAGCCTGCTCCAGCTTCTCCTGGTGGTCGTTCATGTCLSGGLALLGALICFATCAACAGCCTCCTGGGCCTTTTCTGCAGCCTCTGCGAGAAGTGACAGGCAGAACCTTCACTTGCAAGCATGGGTGTTTTCATCATCVTSGVALKDGPFCMGGCTGTCTTGAATCCTTTCTACAAGGAGTGGGTTCAGGCCCTCTGTGGTTAAAGACTGTATCCATGCTGTGCTCAAGGAGGAACTGGFDVSSFNQTQAWKYCAAATGCTGAATATTCTCCAGAAGAAATGCCTCAGCTTACAAAACATTTATCAGAAAACATTAAAGATAAATTAAAAGGTAATCATGGYPFKDLHSRNYLY GTGAAAAAAAAAAAAAAA DRSLWNSVCLEPSA AVVWHVSLFSALLCISLLQLLLVVVHVI NSLLGLFCSLCEK SEQ ID NO.: 5 SEQ ID NO.: 52CCACGCGTCCGCACTTCCAGGGTCGGGGAGACGGAACTGCGGCGACCATGTATTTCTGGTTTATCAAACCGCTAACACCCAGTCTAAMALVPYEETTEFGLGGGCAGGTTCTGTCCCATTGTTATCACTATCGAAGCAGCCGATGGAGGAGGGGAGGTCTGAGCAGAGGGCGGGGTGCAGGCGGAATGQKFHKPLATFSFANGCCCTCGTGCCCTATGAGGAGACCACGGAATTTGGGTTGCAGAAATTCCACAAGCCTCTTGCAACTTTTTCCTTTGCAAACCACACGHTIQIRQDWRHLGVATCCAGATCCGGCAGGACTGGAGACACCTGGGAGTCGCAGCGGTGGTTTGGGATGCGGCCATCGTTCTTTCCACATACCTGGAGATGAAVVWDAAIVLSTYGGAGCTGTGGAGCTCAGGGGCCGCTCTGCCGTGGAGCTGGGTGCTGGCACGGGGCTGGTGGGCATAGTGGCTGCCCTGCTGGGTGCTLEMGAVELRGRSAVCATGTGACTATCACGGATCGAAAAGTAGCATTAGAATTTCTTAAATCAAACGTTCAAGCCAACTTACCTCCTCATATCCAAACTAAAELGAGTGLVGIVAAACTGTTGTTAAGGAGCTGACTTGGGGACAAAATTTGGGGAGTTTTTCTCCTGGAGAATTTGACCTGATACTTGGTGCTGATATCATALLGAHVTITDRKVATATTTAGAAGAAACATTCACAGATCTTCTTCAAACACTGGAACATCTCTGTAGCAATCACTCTGTGATTCTTTTAGCATGCCGAATTLEFLKSNVQANLPPCGCTATGAACGGGATAACAACTTCTTAGCAATGCTGGAGAGGCAATTTATTGTGAGAAAGGTTCACTACGATCCTGAAAAAGATGTAHIQTKTVVKELTWGCATATTTACGAAGCACAGAAGAGAAACCAGAAGGAGGACTTATAATTGGCTATAATTTATAAGAATGTTGTCATTGAGTGTGTCACTQNLGSFSPGEFDLITAAGGTCTTAGACTGCAAATCTAACCATATTTAATGAAATGTCTTACTGTACAAAAAGTCTAAGCCAAAGGTTCTCAGGGGAGAAAGLGADIIYLEETFTDCACATGTGCAGTTTTAAAACAAAGCAGTGCTTTGTCCCATTGCTGTGATTTTTAGTCAGACTTTACTCAGTCTGAAATGCAATTAACLLQTLEHLCSNHSVATTAAAGGATTAAGTGTGAGATTTCGATTTATGCTATTTGTGTATCCCATACTCCTCCCTTTTAATAAACAGTTTCCACTGATGATAILLACRIRYERDNNTGAAGGGCCGGTATAAAGAAGTCTTTAAATGAGTAAGCTTTCTTGGTAAGATTAAATCTTACAAATTATTTTTAAAACCTTGTGATAFLAMLERQFIVRKVTATACAATGTTTAGCTGAGTTTTCTAATTTTCTGGATGTAAAACAAAAGGTTTAACCTATACATTCCTTGAGCTGTTAGTGCTATTTHYDPEKDVHIYEAQAAATCTTTTGCCCTGTTTAGGTCCTAAACACTTTTAGTTGAGTAGGATATGAGCTTTTTTGGGTCTCATATCATGCTTTTTGCCTTAKRNQKEDLATTTCAGGTATATATATATATAAGTAAAGGAATTAAGTAAAAATAAAATTTCAGTTACTTTTTAAAAGCACCTGAAATCTGGCCGGATGCGGTGGCTCATGCCTGTAATCCCACCACTTTGGGAGGCCGAGGCGGGCAGATCACCTGAGGTCGGGAGTTCAAGACCAGCCTGGCCAACATGGTGAAACCCCATCTCTACTAAAAATACAAAAATTAGCCGGGCGTGGTGTCGGGCGCCTGTAGTCCCAGCTGCTCGGGAGGCTGAGGCAGGGGAATCGCTTGAACCTGGGAGGCGGAGGTTGCAGTGAGCTGAGATTGCGCCATTGTACTCCAGCCTGGGGGACAGGAGCGAGACTCCATCTCAAAAAAAAAAAAAAA <SEQ ID NO.: 6 SEQ ID NO.: 53GTGCAGAAGGCACGAGGAAGCCACAGTGCTCCGGATCCTCCAATCTTCGCTCCTCCAATCTCCGCTCCTCCACCCAGTTCAGGAACCMSLLSSRAARVPGPCGCGACCGCTCGCAGCGCTCTCTTGACCACTATGAGCCTCCTGTCCAGCCGCGCGGCCCGTGTCCCCGGTCCTTCGAGCTCCTTGTGSSSLCALLVLLLLLCGCGCTGTTGGTGCTGCTGCTGCTGCTGACGCAGCCAGGGCCCATCGCCAGCGCTGGTCCTGCCGCTGCTGTGTTGAGAGAGCTGCGTQPGPIASAGPAAATTGCGTTTGTTTACAGACCACGCAAGGAGTTCATCCCAAAATGATCAGTAATCTGCAAGTGTTCGCCATAGGCCCACAGTGCTCCAAVLRELRCVCLQTTQGGTGGAAGTGGTAGCCTCCCTGAAGAACGGGAAGGAAATTTGTCTTGATCCAGAAGCCCCTTTTCTAAAGAAAGTCATCCAGAAAATGVHPKMISNLQVFATTTGGACGGTGGAAACAAGGAAAACTGATTAAGAGAAATGAGCACGCATGGAAAAGTTTCCCAGTCTTCAGCAGAGAAGTTTTCTGGIGPQCSKVEVVASLAGGTCTCTGAACCCAGGGAAGACAAGAAGGAAAGATTTTGTTGTTGTTTGTTTATTTGTTTTTCCAGTAGTTAGCTTTCTTCCTGGAKNGKEICLDPEAPFTTCCTCACTTTGAAGAGTGTGAGGAAAACCTATGTTTGCCGCTTAAGCTTTCAGCTCAGCTAATGAAGTGTTTAGCATAGTACCTCTLKKVIQKILDGGNKGCTATTTGCTGTTATTTTATCTGCTATGCTATTGAAGTTTTGGCAATTGACTATAGTGTGAGCCAGGAATCACTGGCTGTTAATCTTENTCAAAGTGTCTTGAATTGTAGGTGACTATTATATTTCCAAGAAATATTCCTTAAGATATTAACTGAGAAGGCTGTGGATTTAATGTGGAAATGATGTTTCATAAGAATTCTGTTGATGGAAATACACTGTTATCTTCACTTTTATAAGAAATAGGAAATATTTTAATGTTTCTTGGGGAATATGTTAGAGAATTTCCTTACTCTTGATTGTGGGATACTATTTAATTATTTCACTTTAGAAAGCTGAGTGTTTCACACCTTATCTATGTAGAATATATTTCCTTATTCAGAATTTCTAAAAGTTTAAGTTCTATGAGGGCTAATATCTTATCTTCCTATAATTTTAGACATTCTTTATCTTTTTAGTATGGCAAACTGCCATCATTTACTTTTAAACTTTGATTTTATATGCTATTTATTAAGTATTTTATTAGGAGTACCATAATTCTGGTAGCTAAATATATATTTTAGATAGATGAAGAAGCTAGAAAACAGGCAAATTCCTGACTGCTAGTTTATATAGAAATGTATTCTTTTAGTTTTTAAAGTAAAGGCAAACTTAACAATGACTTGTACTCTGAAAGTTTTGGAAACGTATTCAAACAATTTGAATATAAATTTATCATTTAGTTATAAAAATATATAGCGACATCCTCGAGGCCCTAGCATTTCTCCTTGGATAGGGGACCAGAGAGAGCTTGGAATGTTAAAAACAAAACAAAACAAAAAAAAACAAGGAGAAGTTGTCCAAGGGATGTCAATTTTTTATCCCTCTGTATGGGTTAGATTTTCCAAAATCATAATTTGAAGAAGGCCAGCATTTATGGTAGAATATATAATTATATATAAGGTGGCCACGCTGGGGCAAGTTCCCTCCCCACTCACAGCTTTGGCCCCTTTCACAGAGTAGAACCTGGGTTAGAGGATTGCAGAAGACGAGCGGCAGCGGGGAGGGCAGGGAAGATGCCTGTCGGGTTTTTAGCACAGTTCATTTCACTGGGATTTTGAAGCATTTCTGTCTGAATGTAAAGCCTGTTCTAGTCCTGGTGGGACACACTGGGGTTGGGGGTGGGGGAAGATGCGGTAATGAAACCGGTTAGTCAGTGTTGTCTTAATATCCTTGATAATGCTGTAAAGTTTATTTTTACAAATATTTCTGTTTAAGCTATTTCACCTTTGTTTGGAAATCCTTCCCTTTTAAAGAGAAAATGTGACACTTGTGAAAAGGCTTGTAGGAAAGCTCCTCCCTTTTTTTCTTTAAACCTTTAAATGACAAACCTAGGTAATTAATGGTTGTGAATTTCTATTTTTGCTTTGTTTTTAATGAACATTTGTCTTTCAGAATAGGATTCTGTGATAATATTTAAATGGCAAAAACAAAACATAATTTTGTGCAATTAACAAAGCTACTGCAAGAAAAATAAAACATTTCTTGGTAAAAACGTATGTATTTATATATTATATATTTATATATAATATATATTATATATTTAGCATTGCTGAGCTTTTTAGATGCCTATTGTGTATCTTTTAAAGGTTTTGACCATTTTGTTATGAGTAATTACATATATATTACATTCACTATATTAAAATTGTACTTTTTTACTATGTGTCTCATTGGTTCATAGTCTTTATTTTGTCCTTTGAATAAACATTAAAAGATTTCTAAACTTCAAAAAAAAAAAAAAAAAA SEQ ID NO.: 7 SEQ ID NO.: 54CTGGACGAGTCCGAGCGCGTCACCTCCTCACGCTGCGGCTGTCGCCCGTGTCCCGCCGGCCCGTTCCGTGTCGCCCCGCAGTGCTGCMAVFVVLLALVAGVGGCCGCCGCGGCACCATGGCTGTGTTTGTCGTGCTCCTGGCGTTGGTGGCGGGTGTTTTGGGGAACGAGTTTAGTATATTAAAATCALGNEFSILKSPGSVCCAGGGTCTGTTGTTTTCCGAAATGGAAATTGGCCTATACCAGGAGAGCGGATCCCAGACGTGGCTGCATTGTCCATGGGCTTCTCTVFRNGNWPIPGERIGTGAAAGAAGACCTTTCTTGGCCAGGACTCGCAGTGGGTAACCTGTTTCATCGTCCTCGGGCTACCGTCATGGTGATGGTGAAGGGAPDVAALSMGFSVKEGTGAACAAACTGGCTCTACCCCCAGGCAGTGTCATTTCGTACCCTTTGGAGAATGCAGTTCCTTTTAGTCTTGACAGTGTTGCAAATDLSWPGLAVGNLFHTCCATTCACTCCTTATTTTCTGAGGAAACTCCTGTTGTTTTGCAGTTGGCTCCCAGTGAGGAAAGAGTGTATATGGTAGGGAAGGCARPRATVMVMVKGVNAACTCAGTGTTTGAAGACCTTTCAGTCACCTTGCGCCAGCTCCGTAATCGCCTGTTTCAAGAAAACTCTGTTCTCAGTTCACTCCCCKLALPPGSVISYPLCTCAATTCTCTGAGTAGGAACAATGAAGTTGACCTGCTCTTTCTTTCTGAACTGCAAGTGCTACATGATATTTCAAGCTTGCTGTCTENAVPFSLDSVANSCGTCATAAGCATCTAGCCAAGGATCATTCTCCTGATTTATATTCACTGGAGCTGGCAGGTTTGGATGAAATTGGGAAGCGTTATGGGIHSLFSEETPVVLQGAAGACTCTGAACAATTCAGAGATGCTTCTAAGATCCTTGTTGACGCTCTGCAAAAGTTTGCAGATGACATGTACAGTCTTTATGGTLAPSEERVYMVGKAGGGAATGCAGTGGTAGAGTTAGTCACTGTCAAGTCATTTGACACCTCCCTCATTAGGAAGACAAGGACTATCCTTGAGGCAAAACAANSVFEDLSVTLRQLGCGAAGAACCCAGCAAGTCCCTATAACCTTGCATATAAGTATAATTTTGAATATTCCGTGGTTTTCAACATGGTACTTTGGATAATGRNRLFQENSVLSSLATCGCCTTGGCCTTGGCTGTGATTATCACCTCTTACAATATTTGGAACATGGATCCTGGATATGATAGCATCATTTATAGGATGACAPLNSLSRNNEVDLLAACCAGAAGATTCGAATGGATTGAATGTTACCTGTGCCAGAATTAGAAAAGGGGGTTGGAAATTGGCTGTTTTGTTAAAATATATCTFLSELQVLHDISSLTTTAGTGTGCTTTAAAGTAGATAGTATACTTTACATTTATAAAAAAAAATCAAATTTTGTTCTTTATTTTGTGTGTGCCTGTGATGTLSRHKHLAKDHSPDTTTTCTAGAGTGAATTATAGTATTGACGTGAATCCCACTGTGGTATAGATTCCATAATATGCTTGAATATTATGATATAGCCATTTALYSLELAGLDEIGKATAACATTGATTTCATTCTGTTTAATGAATTTGGAAATATGCACTGAAAGAAATGTAAAACATTTAGAATAGCTCGTGTTATGGAAARYGEDSEQFRDASKAAAGTGCACTGAATTTATTAGACAAACTTACGAATGCTTAACTTCTTTACACAGCATAGGTGAAAATCATATTTGGGCTATTGTATAILVDALQKFADDMYCTATGAACAATTTGTAAATGTCTTAATTTGATGTAAATAACTCTGAAACAAGAGAAAAGGTTTTTAACTTAGAGTAGCCCTAAAATASLYGGNAVVELVTVTGGATGTGCTTATATAATCGCTTAGTTTTGGAACTGTATCTGAGTAACAGAGGACAGCTGTTTTTTAACCCTCTTCTGCAAGTTTGTKSFDTSLIRKTRTITGACCTACATGGGCTAATATGGATACTAAAAATACTACATTGATCTAAGAAGAAACTAGCCTTGTGGAGTATATAGATGCTTTTCATLEAKQAKNPASPYNTATACACACAAAAATCCCTGAGGGACATTTTGAGGCATGAATATAAAACATTTTTATTTCAGTAACTTTTCCCCCTGTGTAAGTTACLAYKYNFEYSVVFNTATGGTTTGTGGTACAACTTCATTCTATAGAATATTAAGTGGAAGTGGGTGAATTCTACTTTTTATGTTGGAGTGGACCAATGTCTAMVLWIMIALALAVI TCAAGAGTGACAAATAAAGTTAATGATGATTCCAAAAAAAAAAITSYNIWNMDPGYD SIIYRMTNQKIRMD SEQ ID NO.: 8 SEQ ID NO.: 55AGCGGGGCAGCGGCTGCGCCCTGCGCCGGGGCGGAGCCGGGGGCGGGCCGGCGGCCGGCAGGCGGGGGCTGGGGCCCGAGGCCGGGAMEILMTVSKFASICGTGCCTGAGCGCCGGCGGCGACGACGGCAGCGGCGGCCCAGCGGGCTCGGTGGTTGGGTCCGCGGCGGCTCGGGGTCCGCCCGCGGGTMGANASALEKEIGCTGCGGTGCGAGCGGGCGGCCCGGCTCCCCTCCTCCCCCGCCCGCCGCCGCCGCTGTGATTGGGTGGAAGATGGCGCTGGCCGGATGPEQFPVNEHYFGLVGAAATCCTAATGACAGTCTCCAAATTCGCCTCCATCTGTACCATGGGCGCCAATGCTTCGGCATTAGAGAAAGAGATTGGTCCAGAANFGNTCYCNSVLQACAGTTTCCGGTCAATGAGCACTATTTTGGATTAGTCAATTTTGGGAATACCTGCTACTGCAATTCAGTTCTTCAAGCACTTTATTTTLYFCRPFREKVLAYTGTCGTCCATTTCGGGAAAAAGTTCTTGCGTATAAGAGTCAACCTAGGAAAAAGGAGAGCCTTCTTACATGCTTAGCAGATCTCTTCKSQPRKKESLLTCLCATAGCATAGCCACTCAGAAGAAAAAGGTTGGAGTAATACCCCCTAAGAAGTTCATCACAAGATTACGGAAAGAAAATGAGCTTTTTADLFHSIATQKKKVGACAACTACATGCAACAAGATGCCCATGAATTCTTAAATTACCTACTAAATACAATTGCTGATATTTTACAAGAAGAGAGAAAGCAGGVIPPKKFITRLRKGAAAAACAAAATGGTCGTTTACCTAATGGTAATATTGATAATGAAAATAATAACAGCACACCAGACCCAACGTGGGTTGATGAGATTENELFDNYMQQDAHTTTCAGGGAACATTAACTAATGAAACCAGATGTCTTACTTGTGAAACTATAAGCAGCAAAGATGAAGATTTTTTAGACCTTTCTGTTEFLNYLLNTIADILGACGTGGAACAAAATACATCAATTACTCACTGCTTAAGGGGTTTCAGCAACACAGAAACTCTGTGCAGTGAATACAAGTATTACTGTQEERKQEKQNGRLPGAAGAGTGTCGCAGCAAACAGGAAGCACACAAACGGATGAAAGTTAAAAAACTGCCCATGATTCTAGCTCTACACCTGAAGAGATTTNGNIDNENNNSTPDAAATATATGGATCAACTTCATCGATATACAAAACTCTCTTACCGGGTAGTTTTTCCTTTAGAACTTCGTCTGTTTAACACTTCAGGTPTWVDEIFQGTLTNGATGCCACCAATCCAGACAGAATGTACGACCTTGTTGCTGTTGTGGTTCACTGTGGAAGTGGTCCCAATCGAGGCCATTATATTGCAETRCLTCETISSKDATAGTTAAGAGTCATGATTTTTGGTTGTTGTTTGATGACGACATTGTAGAAAAAATAGATGCACAAGCTATTGAAGAATTCTACGGGEDFLDLSVDVEQNTTTGACATCAGATATCTCAAAGAACTCTGAGTCTGGTTACATCCTTTTCTATCAGTCTCGGGACTGAGAGGGAACCGTGATGAAGAGASITHCLRGFSNTETCACTTTCTGCCTCATTTCTTCTCTGGTTATTTTGGAAAGGATCAAGCACTGATTTTTCAAGAAAAGAGAAATGCAGGAAGCTCAGGGLCSEYKYYCEECRSGGCAGTAGCACACTTTGCACACGATAAAGCAAAGACGATGGATTGACAAGCCCTTCCGATCATGGTAGTTGATTTATTTGCTCAGGTKQEAHKRMKVKKLPATCATGCTGTCTGTACAGTTCCATACAACAAGGAGGTGAAATCAGAGATACCAGCTCCTCTTTTAAAACAGCCTTCCAGTCATTGGCMILALHLKRFKYMDACGCATTTTCTCTTTATTAATTGCACCAATAATGCTTTGAATTCCTTGGGGGTGCAGTAGAAAGAATCGGAATCTGTGCCGTATTGAQLHRYTKLSYRVVFTAAGGAGATGATGTTGAACACACTGCATAAATTTGCCTGGTTCAGTATGTATAGAAGCATATTCAGTGGTCTTTTCAAGAGTAAACCPLELRLFNTSGDATAGAAATACTTTTGGGCCCAACACTTGCAGTTGCCTTCCTGATGTAAAAACTAACATGCTAGATAATCCAGTGTCGGGAAGACAAAGANPDRMYDLVAVVVHTGTTTTGCTTCTCTGAAGAAGCTTATAATAATATACAGTATATGTATATGTAGGGAGCAATTGGTCAAAAGTGGCTTTTTGTTTCCCCGSGPNRGHYIAIVCAAGGGGAAAGACTGGCTTTGTAATTATAATTTTTTCCTTATTTATTTTACTTAAAACTGGTAGAGTCTAAGTATTATATGAAGTGCKSHDFWLLFDDDIVCCATGATTCTGTCAGTAAATTTGAACATATTTTTATTAGTTAATGTCAGTTTAAGTTGTCCTTTTGTTTGTTTCTATTTTTAAGGTGEKIDAQAIEEFYGLAATTTTAATTTCTATCTGAAATCAGTTAAGATACCTTGAGAAAAACTGCAGTGAGAGGAGATAAATATCCTTTTTCAGGAGGAACTGTSDISKNSESGYILATATCTCTGGCTAAATATTTGTCCTTTTATTATGGTTTCTAAATCAGTTATTTTCTTCAGCTTTAATTTCATAAAATTAAAAAACTAFYQSRD TTTTAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA SEQ ID NO.: 9 SEQ IDNO.: 56GGAAGCCATTGCCTGTTTAATAGTTGCTGTTGCTGCACTTCCGCTTCTCTCCCAGCGAGAGAGAGACACGAGTGGCCAGGCCCAGCCMSDDDSRASTSSSSGCAGCCGCAGCAGCAGCCGCCGCGGCGGCACGGAGGAGCCAGACACAAAGAGAGGGGCTGTTTGCGGGGTGGGGTGGGGGGTTCGCTSSSSNQQTEKETNTATGTCGGATGACGATTCGAGGGCCAGCACCAGCTCCTCCTCATCTTCGTCTTCCAACCAGCAAACCGAGAAAGAAACAAACACCCCCPKKKESKVSMSKNSAAGAAGAAGGAGAGTAAAGTCAGCATGAGCAAAAACTCCAAACTCCTCTCCACCAGCGCCAAGAGAATTCAGAAGGAGCTGGCGGACKLLSTSAKRIQKELATCACTTTAGACCCTCCACCTAATTGCAGTGCTGGTCCCAAAGGCGATAACATCTATGAATGGAGATCAACCATTCTAGGGCCTCCAADITLDPPPNCSAGGGATCCGTGTATGAGGGTGGTGTATTCTTTCTCGATATCACTTTTACACCAGAATATCCCTTCAAGCCTCCAAAGGTTACATTTCGGPKGDNIYEWRSTILACAAGAATCTATCATTGTAATATTAACAGTCAAGGTGTTATTTGCTTGGACATATTGAAAGATAATTGGAGTCCAGCACTAACCATTGPPGSVYEGGVFFLTCTAAAGTCCTCCTTTCTATCTGCTCACTTCTTACAGACTGTAATCCTGCCGACCCCTTGGTGGGAAGTATTGCCACTCAGTATATGDITFTPEYPFKPPKACCAACAGAGCAGAACATGACAGAATGGCCAGACAGTGGACCAAGAGATACGCTACATAAATTGGGGTTTCACAATTCTTACATTATVTFRTRIYHCNINSTTGTCTGTCACAGAAGAGAGCTGCTTATGATTTTGAAGGGGTCAGGGAGGGTGGGAGTTGGTAAAGAGTAGGGTATTTCTATAACAGQGVICLDILKDNWSATATTATTCAGTCTTATTTCCTAAGATTTTGTTGTAACTTAAGGTATCTTGCTACAGTAGACAGAATTGGTAATAGCAACTTTTAAAPALTISKVLLSICSATTGTCATTAGTTCTGCAATATTAGCTGAAATGTAGTACAGAAAAGAATGTACATTTAGACATTTGGGTTCAGTTGCTTGTAGTCTGLLTDCNPADPLVGSTAAATTTAAAACAGCTTAATTTGGTACAGGTTACACATATGGCCATTTATGTAAAGTCCCTCTAAGACTACATACTTTTTGTTTAAAIATQYMTNRAEHDRACAAAATTGGAATTTGTTTTCCCTTCTTGGAAGGGAACATTGATATTTAACAGAGTTTTTAGAGATTGTCATCTCATATATATAAAAMARQWTKRYATTGGACACGTGGCTATAAAACACCATATAAGAGATGAGTAGTGCGTTTTATTTTATATGCCAATCTACTTTGTTTAAAAAAGGTCTGAATCAGGACTTGTGAAAACCTGTAGTGAAATACCTTAAGCTGTTAACTAACTGTAAGGCGTGGAATAGGAGTTGCTCAGTGGATTGGTTCTATGTTGTGGACTACTTAAGTCTGCATTTGTTACTGTGCTAATAAACAATATTAAAAACCACCTAATAAACAAAAAAAAAAAAAASEQ ID NO.: 10 SEQ ID NO.: 57TTGCTTTCCTCTGCCGCATGGTCCTGGGCCGTTGGCGTCGGAAGCCTGAAGCATGGGCGCTGAGTGGGAGCTGGGGGCCGAGGCTGGMGAEWELGAEAGGSCGGTTCGCTGCTGCTGTGCGCCGCGCTGCTGGCGGCGGGCTGCGCCCTGGGCCTGCGCCTGGGCCGCGGGCAGGGGGCGGCGGACCGLLLCAALLAAGCALCGGGGCGCTCATCTGGCTCTGCTACGACGCGCTGGTGCACTTCGCGCTGGAAGGCCCTTTTGTCTACTTGTCTTTAGTAGGAAACGTGLRLGRGQGAADRGTGCAAATTCCGATGGCTTGATTGCTTCTTTATGGAAAGAATATGGCAAAGCTGATGCAAGATGGGTTTATTTTGATCCAACCATTGTALIWLCYDALVHFAGTCTGTGGAAATTCTGACCGTCGCCCTGGATGGGTCTCTGGCATTGTTCCTCATTTATGCCATAGTCAAAGAAAAATATTACCGGCALEGPFVYLSLVGNVTTTCCTGCAGATCACCCTGTGCGTGTGCGAGCTGTATGGCTGCTGGATGACCTTCCTCCCAGAGTGGCTCACCAGAAGCCCCAACCTANSDGLIASLWKEYCAACACCAGCAACTGGCTGTACTGTTGGCTTTACCTGTTTTTTTTTAACGGTGTGTGGGTTCTGATCCCAGGACTGCTACTGTGGCAGKADARWVYFDPTIGTCATGGCTAGAACTCAAGAAAATGCATCAGAAAGAAACCAGTTCAGTGAAGAAGTTTCAGTGAACTTTCAAAACCATAAACACCATVSVEILTVALDGSLTATCTAACTTCATGAACCAGAATGAATCAAATCTTTTTGTTTGGCCAAAATGTAATACATTCCAGTCTACACTTTGTTTTTGTATTGALFLIYAIVKEKYYTTGCTCCTGAACAACCTGTTTCAAATTGGTTTTAAGGCGACCAGTTTTCGTTGTATTGTTGTTCAATTAAATGGTGATATAGGGAAARHFLQITLCVCELYAGAGAACAAATTTGAATTTGTAATAATAAAATGTTTAATTATACAAAAAAAAAAAAAAAAAGCWMTFLPEWLTRS PNLNTSNWLYCWLY LFFFNGVWVLIPGL LLWQSWLELKKMHQ KETSSVKKFQSEQ ID NO.: 11 SEQ ID NO.: 58GGTCGTTTTCTGATGTGACGGCTGAGACATGAGATCTTCAGCCTCCAGGCTCTCCAGTTTTTCGTCGAGAGATTCACTATGGAATCGMRSSASRLSSFSSRGATGCCGGACCAGATCTCTGTCTCGGAGTTCATCGCCGAGACCACCGAGGACTACAACTCGCCCACCACGTCCAGCTTCACCACGCGDSLWNRMPDQISVSGCTGCACAACTGCAGGAACACCGTCACGCTGCTGGAGGAGGCTCTAGACCAAGATAGAACAGCCCTTCAGAAAGTGAAGAAGTCTGTEFIAETTEDYNSPTAAAAGCAATATATAATTCTGGTCAAGATCATGTACAAAATGAAGAAAACTATGCACAAGTTCTTGATAAGTTTGGGAGTAATTTTTTTSSFTTRLHNCRNTAAGTCGAGACAACCCCGACCTTGGCACCGCGTTTGTCAAGTTTTCTACTCTTACAAAGGAACTGTCCACACTGCTGAAAAATCTGCTVTLLEEALDQDRTACCAGGGTTTGAGCCACAATGTGATCTTCACCTTGGATTCTTTGTTAAAAGGAGACCTAAAGGGAGTCAAAGGAGATCTCAAGAAGCCLQKVKKSVKAIYNSATTTGACAAAGCCTGGAAAGATTATGAGACAAAGTTTACAAAAATTGAGAAAGAGAAAAGAGAGCACGCAAAACAACATGGGATGATGQDHVQNEENYAQVCCGCACAGAGATAACAGGAGCTGAGATTGCGGAAGAAATGGAGAAGGAAAGGCGCCTCTTTCAGCTCCAAATGTGTGAATATCTCATLDKFGSNFLSRDNPTAAAGTTAATGAAATCAAGACCAAAAAGGGTGTGGATCTGCTGCAGAATCTTATAAAGTATTACCATGCACAGTGCAATTTCTTTCADLGTAFVKFSTLTKAGATGGCTTGAAAACAGCTGATAAGTTGAAACAGTACATTGAAAAACTGGCTGCTGATTTATATAATATAAAACAGACCCAGGATGAELSTLLKNLLQGLSAGAAAAGAAACAGCTAACTGCACTCCGAGACTTAATAAAATCCTCTCTTCAACTGGATCAGAAAGAAGATTCTCAGAGCCGGCAAGGHNVIFTLDSLLKGDAGGATACAGCATGCATCAGCTCCAGGGCAATAAGGAATATGGCAGTGAAAAGAAGGGGTACCTGCTAAAGAAAAGTGACGGGATCCGLKGVKGDLKKPFDKGAAAGTATGGCAGAGGAGGAAGTGTTCAGTCAAGAATGGGATTCTGACCATCTCACATGCCACATCTAACAGGCAACCAGCCAAGTTAWKDYETKFTKIEKGAACCTTCTCACCTGCCAAGTAAAACCTAATGCCGAAGACAAAAAATCTTTTGACCTGATATCACATAATAGAACATATCACTTTCAEKREHAKQHGMIRTGGCAGAAGATGAGCAGGATTATGTAGCATGGATATCAGTATTGACAAATAGCAAAGAAGAGGCCCTAACCATGGCCTTCCGTGGAGAEITGAEIAEEMEKEGCAGAGTGCGGGAGAGAACAGCCTGGAAGACCTGACAAAAGCCATTATTGAGGATGTCCAGCGGCTCCCAGGGAATGACATTTGCTGRRLFQLQMCEYLIKCGATTGTGGCTCATCAGAACCCACCTGGCTTTCAACCAACTTGGGTATTTTGACCTGTATAGAATGTTCTGGCATCCATAGGGAAATVNEIKTKKGVDLLQGGGGGTTCATATTTCTCGCATTCAGTCTTTGGAACTAGACAAATTAGGAACTTCTGAACTCTTGCTGGCCAAGAATGTAGGAAACAANLIKYYHAQCNFFQTAGTTTTAATGATATTATGGAAGCAAATTTACCCAGCCCCTCACCAAAACCCACCCCTTCAAGTGATATGACTGTACGAAAAGAATADGLKTADKLKQYIETATCACTGCAAAGTATGTAGATCATAGGTTTTCAAGGAAGACCTGTTCAACTTCATCAGCTAAACTAAATGAATTGCTTGAGGCCATKLAADLYNIKQTQDCAAATCCAGGGATTTACTTGCACTAATTCAAGTCTATGCAGAAGGGGTAGAGCTAATGGAACCACTGCTGGAACCTGGGCAGGAGCTEEKKQLTALRDLIKTGGGGAGACAGCCCTTCACCTTGCCGTCCGAACTGCAGATCAGACATCTCTCCATTTGGTTGACTTCCTTGTACAAAACTGTGGGAASSLQLDQKEDSQSRCCTGGATAAGCAGACGGCCCTGGGAAACACAGTTCTACACTACTGTAGTATGTACAGTAAACCTGAGTGTTTGAAGCTTTTGCTCAGQGGYSMHQLQGNKEGAGCAAGCCCACTGTGGATATAGTTAACCAGGCTGGAGAAACTGCCCTAGACATAGCAAAGAGACTAAAAGCTACCCAGTGTGAAGAYGSEKKGYLLKKSDTCTGCTTTCCCAGGCTAAATCTGGAAAGTTCAATCCACACGTCCACGTAGAATATGAGTGGAATCTTCGACAGGAGGAGATAGATGAGIRKVWQRRKCSVKGAGCGATGATGATCTGGATGACAAACCAAGCCCTATCAAGAAAGAGCGCTCACCCAGACCTCAGAGCTTCTGCCACTCCTCCAGCATNGILTISHATSNRQCTCCCCCCAGGACAAGCTGGCACTGCCAGGATTCAGCACTCCAAGGGACAAACAGCGGCTCTCCTATGGAGCCTTCACCAACCAGATPAKLNLLTCQVKPNCTTCGTTTCCACAAGCACAGACTCGCCCACATCACCAACCACGGAGGCTCCCCCTCTGCCTCCTAGGAACGCCGGGAAAGGTCCAACAEDKKSFDLISHNRTGGCCCACCTTCAACACTCCCTCTAAGCACCCAGACCTCTAGTGGCAGCTCCACCCTATCCAAGAAGAGGCCTCCTCCCCCACCACCTYHFQAEDEQDYVACGGACACAAGAGAACCCTATCCGACCCTCCCAGCCCACTACCTCATGGGCCCCCAAACAAAGGCGCAGTTCCTTGGGGTAACGATGGWISVLTNSKEEALTGGGTCCATCCTCTTCAAGTAAGACTACAAACAAGTTTGAGGGACTATCCCAGCAGTCGAGCACCAGTTCTGCAAAGACTGCCCTTGGMAFRGEQSAGENSLCCCAAGAGTTCTTCCTAAACTACCTCAGAAAGTGGCACTAAGGAAAACAGATCATCTCTCCCTAGACAAAGCCACCATCCCGCCCGAEDLTKAIIEDVQRLAATCTTTCAGAAATCATCACAGTTGGCAGAGTTGCCACAAAAGCCACCACCTGGAGACCTGCCCCCAAAGCCCACAGAACTGGCCCCPGNDICCDCGSSEPCAAGCCCCAAATTGGAGATTTGCCGCCTAAGCCAGGAGAACTGCCCCCCAAACCACAGCTGGGGGACCTGCCACCCAAACCCCAACTTWLSTNLGILTCIECTCAGACTTACCTCCCAAACCACAGATGAAGGACCTGCCCCCCAAACCACAGCTGGGAGACCTGCTAGCAAAATCCCAGACTGGAGACSGIHREMGVHISRTGTCTCACCCAAGGCTCAGCAACCCTCTGAGGTCACACTGAAGTCACACCCATTGGATCTATCCCCAAATGTGCAGTCCAGAGACGCIQSLELDKLGTSELCATCCAAAAGCAAGCATCTGAAGACTCCAACGACCTCACGCCTACTCTGCCAGAGACGCCCGTACCACTGCCCAGAAAAATCAATACLLAKNVGNNSFNDIGGGGAAAAATAAAGTGAGGCGAGTGAAGACCATTTATGACTGCCAGGCAGACAACGATGACGAGCTCACATTCATCGAGGGAGAAGTMEANLPSPSPKPTPGATTATCGTCACAGGGGAAGAGGACCAGGAGTGGTGGATTGGCCACATCGAAGGACAGCCTGAAAGGAAGGGGGTCTTTCCAGTGTCSSDMTVRKEYITAKCTTTGTTCATATCCTGTCTGACTAGCAAAACGCAGAACCTTAAGATTGTCCACATCCTTCATGCAAGACTGCTGCCTTCATGTAACCYVDHRFSRKTCSTSCTGGGCACAGTGTGTATATAGCTGCTGTTACAGAGTAAGAAACTCATGGAAGGGCCACCTCAGGAGGGGGATATAATGTGTGTTGTASAKLNELLEAIKSRAATATCCTGTGGTTTTCTGCCTTCACCAGTATGAGGGTAGCCTCGGACCCGGCGCGCCTTACTGGTTTGCCAAAGCCATCCTTGGCADLLALIQVYAEGVETCTAGCACTTACATCTCTCTATGCTGTTCTACAAGCAAACAAACAAAAATAGGAGTATAGGAACTGCTGGCTTTGCAAATAGAAGTGLMEPLLEPGQELGEGTCTCCAGCAACCGTTGAAAGGCATAGAATTGACTCTGTTCCTAACAATGCAGTATTCTCAATTGTGTTACTGAAAATGCAACATTATALHLAVRTADQTSGCAAAGAGGTGGGTTCTGTTTTCCAGGTGAAACTTTTAGCTCCATGACAGACCAGCCTGTAGTTATCTGTGTACACAGTTTACAGCTLHLVDFLVQNCGNLACAAAAACCTACTTTGGTATTTATTACAGAAAAGTGCTCAGTTAATGTAAGTGTTATTCCTTCAGCAAAATATTCACTGACCCAAAADKQTALGNTVLHYCCTCTTTATGGCATTTTACAATGCACACAGCCTCATGCAAGTTTAGACAAGTGGATTTATACTGTCTTATGAGTGCCCGCCCCTGATASMYSKPECLKLLLRTATTACCTCATTATGCAAAAATAACATATCTTTCATGACTATTTTGACAAAAGTTTAAAACACATATGAAGTTCAAATTTCAGGAACSKPTVDIVNQAGETCAAGGACTGCCAGAAAATATTAGCCTCTACATTACGCATGCATTTAGAAGCTTACCTGAAATCTGCCTTTTATAAAGGAATAGTATGALDIAKRLKATQCEGATAAGTGGAATTGTACATTTTTTAAACTTGATTGCCATTAAAGCAGAAATTATAAGGTTGCAACAATATTTGTTTCTAATCACTGGDLLSQAKSGKFNPHCTTTCTCAAGAGTATGGATTGACATATTGTGTTATGAATGCACATCTCTCAGATGTGTTGAAGCATCCATTGCATCCATTTTTTATTVHVEYEWNLRQEEIATTTTCTTAGTTTTGTTCTTGGACAAATTTAAACTTTTAAAAGATTATTCAAGATGAATTTAAAAGTCAACCCTTCACACAGTTTCCDESDDDLDDKPSPICTACTGTATGTAGAATCCAGGTGCTGAAACCAAGTGTTTCTTTTCCCATGCTCTTTGTTAAACCCCAATTATAGATAATTTTTCCAGKKERSPRPQSFCHSTCTTAAGCTCTGTCCACCTTCAAGTCAATTCATAACCAAGTTTTTGAACGCTGCTATGAATTGCACTGTGAAAAGCACTCTTCCCTCSSISPQDKLALPGFTCAGTTTTCTTTTCATCCCAGCCATGTTTATCAGATCCTTAAGAACATTGTATTTCAGTCTTTTACATCAGTCTGAATTTTGGAAAASTPRDKQRLSYGAFGAATGCAATAGTTGTACTCCACAGTCAGTGGAACTGTTCCCTGAGTCCGAGGCTCATGTGTCATTCTGGCACTACATTTGCTTAAATTNQIFVSTSTDSPTTGCTATTTTGGCAACAGCACAGAAAACTAATATTTTTAAGCAGAGAATCTTGGCAATGAGTGAGAGATGTTAATTTCACAGAAGCACSPTTEAPPLPPRNAAACTCCCAACCCAACCCTTAGGAAAAGCCCTCTTCCATCGTTACAGTGCTCAGTGAATATTAATTTAGTTCTGCTTAAGTGGTTGCTGKGPTGPPSTLPLSATACAAACTTTGAATAGCCACCTAATAAATAAACCTTGCATGACAAACCTGCAAAATATTTTATCAGCTGTTATTGGAAAGTGATTTTQTSSGSSTLSKKRTAAGCAATTGCTTCCTCAGTGTCAGGGCACATGTGAATTTCCACACCAAACAGAGCATGAGGAACCAGTTGACATGCTGGGTTGTGAPPPPPPGHKRTLSDCTGGCAGCTTTAGCAGCCTCGGTACTGAAGCCACACCAGTGTCCGGATGGAAGTCTGCATCTGAGGTTGCTCAGTGTCCCGGTCATTPPSPLPHGPPNKGACATTTACACATTTTAACTTGCATTAAAGAGCTGTTCTTTTCTGTGGCCTAGACTCTTTTCACTGATCTCAAAATAAACTGGTTTTTTVPWGNDGGPSSSSKTCAAAAAAAAAAAAAAAACAAAAACAAAAAAAAAACACAAAAGCTGCATGTCTAAAATTACATGGAGTTAGTGTCTATTCTTTTTCCTTNKFEGLSQQSSTCCTTTTGCAGCAACTTACACAGCATTTTTAACACCTTTTTTTTCTAGTTTTTTTGTTCGGTTTTGTTTTCCATCAGGAATTTGAGTTSSAKTALGPRVLPKCTCTCTAACCCAGCTTACTGTGGGACATAGGAAAACTCAGTAGAAATACCTTTGGTGATCTTGTTGAGTTTAAGTCTGATCTTGATCLPQKVALRKTDHLSTTAAACTCAGTAAGCCACTATCTGCAATTTTGTACATTATATAGTATTTTGAAGATATGGAACCTTATGAAAAAAAAATAGCAAATTLDKATIPPEIFQKSAGTTCTTTTTCCCCCAGAGGGGAAAGTTATGTTCTGCAAATAGTGTGTGTCTTATTTTACTGTTGAACAGCAATTGCTATTTATTTTSQLAELPQKPPPGDTTTATTGCCTAGAACTTCAACATGTTGTATAGGAATCCTGTAGTGCCACTAGTTAAATGCCGAATTCTCATCTGGATGTTACCATCALPPKPTELAPKPQIAACATCAGTACACTTGTCATTTCACATGTGTTTAATGTGACAGTTTTTCAGTACTGTATGTGTTAATTTCTACTTTTTTTAATATTTGDLPPKPGELPPKP AAAATTGCTTTTAAATAAACATATTCTCAGTTGATCCC QLGDLPPKPQLSDLPPKPQMKDLPPKPQ LGDLLAKSQTGDVS PKAQQPSEVTLKSH PLDLSPNVQSRDAIQKQASEDSNDLTPT LPETPVPLPRKINT GKNKVRRVKTIYDC QADNDDELTFIEGEVIIVTGEEDQEWWI GHIEGQPERKGVFP VSFVHILSD SEQ ID NO.: 12 SEQ ID NO.: 59CTTCCAGAGAGCAATATGGCTGGTTCCCCAACATGCCTCACCCTCATCTATATCCTTTGGCAGCTCACAGGGTCAGCAGCCTCTGGAMAGSPTCLTLIYILCCCGTGAAAGAGCTGGTCGGTTCCGTTGGTGGGGCCGTGACTTTCCCCCTGAAGTCCAAAGTAAAGCAAGTTGACTCTATTGTCTGGWQLTGSAASGPVKEACCTTCAACACAACCCCTCTTGTCACCATACAGCCAGAAGGGGGCACTATCATAGTGACCCAAAATCGTAATAGGGAGAGAGTAGACLVGSVGGAVTFPLKTTCCCAGATGGAGGCTACTCCCTGAAGCTCAGCAAACTGAAGAAGAATGACTCAGGGATCTACTATGTGGGGATATACAGCTCATCASKVKQVDSIVWTFNCTCCAGCAGCCCTCCACCCAGGAGTACGTGCTGCATGTCTACGAGCACCTGTCAAAGCCTAAAGTCACCATGGGTCTGCAGAGCAATTTPLVTIQPEGGTIAAGAATGGCACCTGTGTGACCAATCTGACATGCTGCATGGAACATGGGGAAGAGGATGTGATTTATACCTGGAAGGCCCTGGGGCAAIVTQNRNRERVDFPGCAGCCAATGAGTCCCATAATGGGTCCATCCTCCCCATCTCCTGGAGATGGGGAGAAAGTGATATGACCTTCATCTGCGTTGCCAGGDGGYSLKLSKLKKNAACCCTGTCAGCAGAAACTTCTCAAGCCCCATCCTTGCCAGGAAGCTCTGTGAAGGTGCTGCTGATGACCCAGATTCCTCCATGGTCDSGIYYVGIYSSSLCTCCTGTGTCTCCTGTTGGTGCCCCTCCTGCTCAGTCTCTTTGTACTGGGGCTATTTCTTTGGTTTCTGAAGAGAGAGAGACAAGAAQQPSTQEYVLHVYEGAGTACATTGAAGAGAAGAAGAGAGTGGACATTTGTCGGGAAACTCCTAACATATGCCCCCATTCTGGAGAGAACACAGAGTACGACHLSKPKVTMGLQSNACAATCCCTCACACTAATAGAACAATCCTAAAGGAAGATCCAGCAAATACGGTTTACTCCACTGTGGAAATACCGAAAAAGATGGAAKNGTCVTNLTCCMEAATCCCCACTCACTGCTCACGATGCCAGACACACCAAGGCTATTTGCCTATGAGAATGTTATCTAGACAGCAGTGCACTCCCCTAAGHGEEDVIYTWKALGTCTCTGCTCAAAAAAAAAACAATTCTCGGCCCAAAGAAAACAATCAGAAGAATTCACTGATTTGACTAGAAACATCAAGGAAGAATGQAANESHNGSILPIAAGAACGTTGACTTTTTTCCAGGATAAATTATCTCTGATGCTTCTTTAGATTTAAGAGTTCATAATTCCATCCACTGCTGAGAAATCSWRWGESDMTFICVTCCTCAAACCCAGAAGGTTTAATCACTTCATCCCAAAAATGGGATTGTGAATGTCAGCAAACCATAAAAAAAGTGCTTAGAAGTATTARNPVSRNFSSPILCCTATAGAAATGTAAATGCAAGGTCACACATATTAATGACAGCCTGTTGTATTAATGATGGCTCCAGGTCAGTGTCTGGAGTTTCATARKLCEGAADDPDSTCCATCCCAGGGCTTGGATGTAAGGATTATACCAAGAGTCTTGCTACCAGGAGGGCAAGAAGACCAAAACAGACAGACAAGTCCAGCSMVLLCLLLVPLLLAGAAGCAGATGCACCTGACAAAAATGGATGTATTAATTGGCTCTATAAACTATGTGCCCAGCACTATGCTGAGCTTACACTAATTGGSLFVLGLFLWFLKRTCAGACGTGCTGTCTGCCCTCATGAAATTGGCTCCAAATGAATGAACTACTTTCATGAGCAGTTGTAGCAGGCCTGACCACAGATTCERQEEYIEEKKRVDCCAGAGGGCCAGGTGTGGATCCACAGGACTTGAAGGTCAAAGTTCACAAAGATGAAGAATCAGGGTAGCTGACCATGTTTGGCAGATICRETPNICPHSGEACTATAATGGAGACACAGAAGTGTGCATGGCCCAAGGACAAGGACCTCCAGCCAGGCTTCATTTATGCACTTGTGCTGCAAAAGAAANTEYDTIPHTNRTIAGTCTAGGTTTTAAGGCTGTGCCAGAACCCATCCCAATAAAGAGACCGAGTCTGAAGTCACATTGTAAATCTAGTGTAGGAGACTTGLKEDPANTVYSTVEGAGTCAGGCAGTGAGACTGGTGGGGCACGGGGGGCAGTGGGTACTTGTAAACCTTTAAAGATGGTTAATTCATTCAATAGATATTTAIPKKMENPHSLLTMTTAAGAACCTATGCGGCCCGGCATGGTGGCTCACACCTGTAATCCCAGCACTTTGGGAGGCCAAGGTGGGTGGGTCATCTGAGGTCAPDTPRLFAYENVIGGAGTTCAAGACCAGCCTGGCCAACATGGTGAAACCCCATCTCTACTAAAGATACAAAAATTTGCTGAGCGTGGTGGTGTGCACCTGTAATCCCAGCTACTCGAGAGGCCAAGGCATGAGAATCGCTTGAACCTGGGAGGTGGAGGTTGCAGTGAGCTGAGATGGCACCACTGCACTCCGGCCTAGGCAACGAGAGCAAAACTCCAATACAAACAAACAAACAAACACCTGTGCTAGGTCAGTCTGGCACGTAAGATGAACATCCCTACCAACACAGAGCTCACCATCTCTTATACTTAAGTGAAAAACATGGGGAAGGGGAAAGGGGAATGGCTGCTTTTGATATGTTCCCTGACACATATCTTGAATGGAGACCTCCCTACCAAGTGATGAAAGTGTTGAAAAACTTAATAACAAATGCTTGTTGGGCAAGAATGGGATTGAGGATTATCTTCTCTCAGAAAGGCATTGTGAAGGAATTGAGCCAGATCTCTCTCCCTACTGCAAAACCCTATTGTAGTAAAAAAGTCTTCTTTACTATCTTAATAAAACAGATATTGTGAGATTCAAAAAAAAAAAAAAAA SEQ IDNO.: 13 SEQ ID NO.: 60GACTGCGCGGCCGGGAGGAGCCGAGCCGGGCGGCGGCGGCGGGAGGCTACAGCGCGCGGGGGTCTCCCGCGTCCCCTCCGCCTCGCCMSSDRQRSDDESPSGGGAGCTCGCGCCCTCGCCCAGCCGAGCTCCCACCCCCGCTTTTTTCCGAAGGCGCTGGGCGGCGCCACCCTCCGGCCGGAGCCCGGTSSGSSDADQRDPACACTGCACAACCCCCTCCGACTTTCAATGTTCCACACTCCCCGGCCAGAGCCTCCTCGGCTTCTTTTTTTCCCTCCCCCCCCTTCCCAPEPEEQEERKPSACCCCCCACAGCTGCCTCCATTTCCTTAAGGAAGGGTTTTTTTCTCTCTCCCTCCCCCACACCGTAGCGGCGCGCGAGCGGGCCGGGCTQQKKNTKLSSKTTGGGCGGCCGAGTTTTCCAAGAGATAACTTCACCAAGATGTCCAGTGATAGGCAAAGGTCCGATGATGAGAGCCCCAGCACCAGCAGTAKLSTSAKRIQKELGGCAGTTCAGATGCGGACCAGCGAGACCCAGCCGCTCCAGAGCCTGAAGAACAAGAGGAAAGAAAACCTTCTGCCACCCAGCAGAAGAEITLDPPPNCSAGAAAAACACCAAACTCTCTAGCAAAACCACTGCTAAGTTATCCACTAGTGCTAAAAGAATTCAGAAGGAGCTAGCTGAAATAACCCTTPKGDNIYEWRSTILGATCCTCCTCCTAATTGCAGTGCTGGGCCTAAAGGAGATAACATTTATGAATGGAGATCAACTATACTTGGTCCACCGGGTTCTGTAGPPGSVYEGGVFFLTATGAAGGTGGTGTGTTTTTTCTGGATATCACATTTTCATCAGATTATCCATTTAAGCCACCAAAGGTTACTTTCCGCACCAGAATCDITFSSDYPFKPPKTATCACTGCAACATCAACAGTCAGGGAGTCATCTGTCTGGACATCCTTAAAGACAACTGGAGTCCCGCTTTGACTATTTCAAAGGTTVTFRTRIYHCNINSTTGCTGTCTATTTGTTCCCTTTTGACAGACTGCAACCCTGCGGATCCTCTGGTTGGAAGCATAGCCACTCAGTATTTGACCAACAGAQGVICLDILKDNWSGCAGAACACGACAGGATAGCCAGACAGTGGACCAAGAGATACGCAACATAATTCACATAATTTGTATGCAGTGTGAAGGAGCAGAAGPALTISKVLLSICSGCATCTTCTCACTGTGCTGCAAATCTTTATAGCCTTTACAATACGGACTTCTGTGTATATGTTATACTGATTCTACTCTGCTTTTATLLTDCNPADPLVGSCCTTTGGAGCCTGGGAGACTCCCCAAAAAGGTAAATGCTATCAAGAGTAGAACTTTGTAGCTGTAGATTAGTTATGTTTAAAACGCCIATQYLTNRAEHDRTACTTGCAAGTCTTGCTTCTTTGGGATATCAAAATGTATTTTGTGATGTACTAAGGATACTGGTCCTGAAGTCTACCAAATATTATAIARQWTKRYATGTGCATTTTAGCCTAATTCATTATCTGTATGAAGTTATAAAAGTAGCTGTAGATGGCTAGGAATTATGTCATTTGTATTAAACCCAGATCTATTTCTGAGTATGTGGTTCATGCTGTTGTGAAAAATGTTTTACCTTTTACCTTTGTCAGTTTGTAATGAGAGGATTTCCTTTTACCCTTTGTAGCTCAGAGAGCACCTGATGTATCATCTCAAACACAATAAACATGCTCCTGAAGGAAAAAAAAAAAAAAAASEQ ID NO.: 14 SEQ ID NO.: 61CCACGCGTCCGGGACCCGGCCCGCGCCTTCTGCCCCTGCTGCCGGCCGCGCCATGCGGTGAGCGCCCCAGGCCGCCAGAGCCCACCCMARGSALLLASLLLGACCCGGCCCGACGCCCGGACCTGCCGCCCAGACCCGCCACCGCACCCGGACCCCGACGCTCCGAACCCGGGCGCAGCCGCAGCTCAAAALSASAGLWSPAAGATGGCCCGAGGCAGCGCCCTCCTTCTCGCCTCCCTCCTCCTCGCCGCGGCCCTTTCTGCCTCTGCGGGGCTCTGGTCGCCGGCCAKEKRGWTLNSAGYLAGGAAAAACGAGGCTGGACCCTGAACAGCGCGGGCTACCTGCTGGGCCCACATGCCGTTGGCAACCACAGGTCATTCAGCGACAAGALGPHAVGNHRSFSDATGGCCTCACCAGCAAGCGGGAGCTGCGGCCCGAAGATGACATGAAACCAGGAAGCTTTGACAGGTCCATACCTGAAAACAATATCAKNGLTSKRELRPEDTGCGCACAATCATTGAGTTTCTGTCTTTCTTGCATCTCAAAGAGGCCGGTGCCCTCGACCGCCTCCTGGATCTCCCCGCCGCAGCCTDMKPGSFDRSIPENCCTCAGAAGACATCGAGCGGTCCTGAGAGCCTCCTGGGCATGTTTGTCTGTGTGCTGTAACCTGAAGTCAAACCTTAAGATAATGGANIMRTIIEFLSFLHTAATCTTCGGCCAATTTATGCAGAGTCAGCCATTCCTGTTCTCTTTGCCTTGATGTTGTGTTGTTATCATTTAAGATTTTTTTTTTTLKEAGALDRLLDLPTGGTAATTATTTTGAGTGGCAAAATAAAGAATAGCAATTAAAAAAAAAAAAACAAAAAAAAAAAAAAAAAAASSEDIERS SEQ ID NO.: 15 SEQ ID NO.: 62CGGTGGTTGGGTGGTAAGATGGCGGCTGTGAGTCTGCGGCTCGGCGACTTGGTGTGGGGGAAACTCGGCCGATATCCTCCTTGGCCAMAAVSLRLGDLVWGGGAAAGATTGTTAATCCACCAAAGGACTTGAAGAAACCTCGCGGAAAGAAATGCTTCTTTGTGAAATTTTTTGGAACAGAAGATCATKLGRYPPWPGKIVNGCCTGGATCAAAGTGGAACAGCTGAAGCCATATCATGCTCATAAAGAGGAAATGATAAAAATTAACAAGGGTAAACGATTCCAGCAAPPKDLKKPRGKKCFGCGGTAGATGCTGTCGAAGAGTTCCTCAGGAGAGCCAAAGGGAAAGACCAGACGTCATCCCACAATTCTTCTGATGACAAGAATCGAFVKFFGTEDHAWIKCGTAATTCCAGTGAGGAGAGAAGTAGGCCAAACTCAGGTGATGAGAAGCGCAAACTTAGCCTGTCTGAAGGGAAGGTGAAGAAGAACVEQLKPYHAHKEEMATGGGAGAAGGAAAGAAGAGGGTGTCTTCAGGCTCTTCAGAGAGAGGCTCCAAATCCCCTCTGAAAAGAGCCCAAGAGCAAAGTCCCIKINKGKRFQQAVDCGGAAGCGGGGTCGGCCCCCAAAGGATGAGAAGGATCTCACCATCCCGGAGTCTAGTACCGTGAAGGGGATGATGGCCGGACCGATGAVEEFLRRAKGKDQGCCGCGTTTAAATGGCAGCCAACCGCAAGCGAGCCTGTTAAAGATGCAGATCCTCATTTCCATCATTTCCTGCTAAGCCAAACAGAGTSSHNSSDDKNRRNAAGCCAGCTGTCTGTTACCAGGCAATCACGAAGAAGTTGAAAATATGTGAAGAGGAAACTGGCTCCACCTCCATCCAGGCAGCTGACSSEERSRPNSGDEKAGCACAGCCGTGAATGGCAGCATCACACCCACAGACAAAAAGATAGGATTTTTGGGCCTTGGTCTCATGGGAAGTGGAATCGTCTCCRKLSLSEGKVKKNMAACTTGCTAAAAATGGGTCACACAGTGACTGTCTGGAACCGCACTGCAGAGAAATGTGATTTGTTCATCCAGGAGGGGGCCCGTCTGGEGKKRVSSGSSERGGAAGAACCCCCGCTGAAGTCGTCTCAACCTGCGACATCACTTTCGCCTGCGTGTCGGATCCCAAGGCGGCCAAGGACCTGGTGCTGGSKSPLKRAQEQSPGGCCCCAGTGGTGTGCTGCAAGGGATCCGCCCTGGGAAGTGCTACGTGGACATGTCAACAGTGGACGCTGACACCGTCACTGAGCTGRKRGRPPKDEKDLTGCCCAGGTGATTGTGTCCAGGGGGGGGCGCTTTCTGGAAGCCCCCGTCTCAGGGAATCAGCAGCTGTCTAATGACGGGATGTTGGTGIPESSTVKGMMAGPATCTTAGCGGCTGGAGACAGGGGCTTATATGAGGACTGCAGCAGCTGCTTCCAGGCGATGGGGAAGACCTCCTTCTTCCTAGGTGAAMAAFKWQPTASEPVGTGGGCAATGCAGCCAAGATGATGCTGATCGTGAACATGGTCCAAGGGAGCTTCATGGCCACTATTGCCGAGGGGCTGACCCTGGCCKDADPHFHHFLLSQCAGGTGACAGGCCAGTCCCAGCAGACACTCTTGGACATCCTCAATCAGGGACAGTTGGCCAGCATCTTCCTGGACCAGAAGTGCCAATEKPAVCYQAITKKAATATCCTGCAAGGAAACTTTAAGCCTGATTTCTACCTGAAATACATTCAGAAGGATCTCCGCTTAGCCATTGCGCTGGGTGATGCGLKICEEETGSTSIQGTCAACCATCCGACTCCCATGGCAGCTGCAGCAAATGAGGTGTACAAAAGAGCCAAGGCGCTGGACCAGTCCGACAACGATATGTCCAADSTAVNGSITPTGCCGTGTACCGAGCCTACATACACTAAGCTGTCGACACCCCGCCCTCACCCCTCCAATCCCCCCTCTGACCCCCTCTTCCTCACATGDKKIGFLGLGLMGSGGGTCGGGGGCCTGGGAGTTCATTCTGGACCAGCCCACCTATCTCCATTTCCTTTTATACAGACTTTGAGACTTGCCATCAGCACAGGIVSNLLKMGHTVTCACACAGCAGCACCCTTCCCCTGAGGCCGGTGGGGAGGGGACAAGTGTCAGCAGGATTGGCGTGTGGGAAAGCTCTTGAGCTGGGCAVWNRTAEKCDLFIQCTGGCCCCCCGGACGAGGTGGCTGTGTGTTCACACACACACACACACACACACACACACACACACACAGGCTCTCGCCCCAGGATAGEGARLGRTPAEVVSAAGCTGCCCAGAAACTGCTGCCTGGCTTTTTTTCTTCCGAGCTTGTCTTATCTCAAACCCCTTCCAGTCAAGGAACTAGAATCAGCATCDITFACVSDPKAACGAGAGTTGGAAGCCTTCCCACAGCTTCCCCCAGAGCGAAGAGGCTGTAGTCATGTCCCCATCCCCCACTGGATTCCCTACAAGGAAKDLVLGPSGVLQGGAGGCCTTGGGCCCAGATGAGCCAGTACAGACTCCAGACAGAGGGGCCCTTGGGGCCCTCCAACCTCAGGTGATGAGCTGAGAAAGAIRPGKCYVDMSTVDTGTTCACGTCTAAGCGTCCAGTGTGCACCCAGCGCTCCATAGACGCCTTTGTGAACTGAAAAGAGACTGGCAGAGTCCCGAGAAGATADTVTELAQVIVSRGGGGCCCTGGCTTTCCAGGGAGTGCAGCAAGCAGCCGGCCTGCAGGTGAGCATGGAGGCCCGGCCCTCACCGCCTCGAAGCCATGCCGGRFLEAPVSGNQQCCAGATGCCACTGCCACAGCGGGCGCTCGCTCCTCCCTAGGCTGTTTTAGTATTTGGATTTGCATTCCATCCCTTGGGAGGGAGTCCLSNDGMLVILAAGDTCAGGGCCACTAGTGATGAGCCAAGAGGAGTGGGGGTTGGGGGCGCTCCTTTCTGTTTCCGTTAGGCCACAGACTCTTCACCTGGCTRGLYEDCSSCFQAMCTGAAGAGCCACTCTTACCTCGGTCCCCTCCCAGTGGTCCCACCTTCTCCACCCTGCCCTGCCAAGTCCCCTGCATGCCCACCGCTCGKTSFFLGEVGNAATCCATCCTCCCTCCTCTCCCTCTTCCTCCCGTGGAGACAGTATTTCTTTCTGTCTGTCCCTTTGGCCCAGACCCAGCCTGACCAACGKMMLIVNMVQGSFMATGAGCATTTCTTAGGCTCAGCTCTTGATACGGAAACGAGTGTCTTCACTCCAGCCAGCATCATGGTCTTCGGTGCTTCCCGGGCCCATIAEGLTLAQVTGGGGGTCTGTCGGGAGGGAAGAGAACTGGGCCTGACCTACCTGAACTGACTGGCCCTCCGAGGTGGGTCTGGGACATCCTAGAGGCCCQSQQTLLDILNQGQTACATTTGTCCTTGGATAGGGGACCGGGGGGGGCTTGGAATGTTGCAAAAAAAAAGTTACCCAAGGGATGTCAGTTTTTTATCCCTCLASIFLDQKCQNILTGCATGGGTTGGATTTTCCAAAATCATAATTTGCAGAAGGAAGGCCAGCATTTACGATGCAATATGTAATTATATATAGGGTGGCCAQGNFKPDFYLKYIQCACTAGGGCGGGGTCCTTCCCCCCTACACAGCTTTGGCCCCTTTCAGAGATTAGAAACTGGGTTAGAGGATTGCAGAAGACGAGTGGKDLRLAIALGDAVNGGGGAGGGCAGGGAAGATGCCTGTCGGGTTTTTAGCACAGTTCATTTCACTGGGATTTTGAAGCATTTCTGTCTGAACACAAGCCTGHPTPMAAAANEVYKTTCTAGTCCTGGCGGAACACACTGGGGGTGGGGGCGGGGGAAGATGCGGTAATGAAACCGGTTAGTCAATTTTGTCTTAATATTGTTRAKALDQSDNDMSAGACAATTCTGTAAAGTTCCTTTTTATGAATATTTCTGTTTAAGCTATTTCACCTTTCTTTTGAAATCCTTCCCTTTTAAGGAGAAAAVYRAYIHTGTGACACTTGTGAAAAAGCTTGTAAGAAAGCCCCTCCCTTTTTTTCTTTAAACCTTTAAATGACAAATCTAGGTAATTAAGGTTGTGAATTTTTATTTTTGCTTTGTTTTTAATGAACATTTGTCTTTCAGAATAGGATTGTGTGATAATGTTTAAATGGCAAAAACAAAACATGATTTTGTGCAATTAACAAAGCTACTGCAAGAAAAATAAAACACTTCTTGGTAACACAAAAAAAAAAAAAAAAAAAASEQ ID NO.: 16 SEQ ID NO.: 63AGTACCTTGGTCCAGCTCTTCCTGCAACGGCCCAGGAGCTCAGAGCTCCACATCTGACCTTCTAGTCATGACCAGGACCAGGGCAGCMTRTRAALLLFTALACTCCTCCTGTTCACAGCCTTAGCAACTTCTCTAGGTTTCAACTTGGACACAGAGGAGCTGACAGCCTTCCGTGTGGACAGCGCTGGATSLGFNLDTEELTGTTTGGAGACAGCGTGGTCCAGTATGCCAACTCCTGGGTGGTGGTTGGAGCCCCCCAAAAGATAACAGCTGCCAACCAAACGGGTGGAFRVDSAGFGDSVVCCTCTACCAGTGTGGCTACAGCACTGGTGCCTGTGAGCCCATCGGCCTGCAGGTGCCCCCGGAGGCCGTGAACATGTCCCTGGGCCTQYANSWVVVGAPQKGTCCCTGGCGTCTACCACCAGCCCTTCCCAGCTGCTGGCCTGCGGCCCCACCGTGCACCACGAGTGCGGGAGGAACATGTACCTCACITAANQTGGLYQCGCGGACTCTGCTTCCTCCTGGGCCCCACCCAGCTCACCCAGAGGCTCCCGGTGTCCAGGCAGGAGTGCCCAAGACAGGAGCAGGACATYSTGACEPIGLQVPTGTGTTCCTGATCGATGGCTCAGGCAGCATCTCCTCCCGCAACTTTGCCACGATGATGAACTTCGTGAGAGCTGTGATAAGCCAGTTPEAVNMSLGLSLASCCAGAGACCCAGCACCCAGTTTTCCCTGATGCAGTTCTCCAACAAATTCCAAACACACTTCACTTTCGAGGAATTCAGGCGCAGCTCTTSPSQLLACGPTVAAACCCCCTCAGCCTGTTGGCTTCTGTTCACCAGCTGCAAGGGTTTACATACACGGCCACCGCCATCCAAAATGTCGTGCACCGATTHHECGRNMYLTGLCGTTCCATGCCTCATATGGGGCCCGTAGGGATGCCGCCAAAATTCTCATTGTCATCACTGATGGGAAGAAAGAAGGCGACAGCCTGGAFLLGPTQLTQRLPVTTATAAGGATGTCATCCCCATGGCTGATGCAGCAGGCATCATCCGCTATGCAATTGGGGTTGGATTAGCTTTTCAAAACAGAAATTCSRQECPRQEQDIVFTTGGAAAGAATTAAATGACATTGCATCGAAGCCCTCCCAGGAACACATATTTAAAGTGGAGGACTTTGATGCTCTGAAAGATATTCALIDGSGSISSRNFAAAACCAACTGAAGGAGAAGATCTTTGCCATTGAGGGTACGGAGACCACAAGCAGTAGCTCCTTCGAATTGGAGATGGCACAGGAGGGTMMNFVRAVISQFQCTTCAGCGCTGTGTTCACACCTGATGGCCCCGTTCTGGGGGCTGTGGGGAGCTTCACCTGGTCTGGAGGTGCCTTCCTGTACCCCCCRPSTQFSLMQFSNKAAATATGAGCCCTACCTTCATCAACATGTCTCAGGAGAATGTGGACATGAGGGACTCTTACCTGGGTTACTCCACCGAGCTGGCCCTFQTHFTFEEFRRSSCTGGAAAGGGGTGCAGAGCCTGGTCCTGGGGGCCCCCCGCTACCAGCACACCGGGAAGGCTGTCATCTTCACCCAGGTGTCCAGGCANPLSLLASVHQLQGATGGAGGATGAAGGCCGAAGTCACGGGGACTCAGATCGGCTCCTACTTCGGGGCCTCCCTCTGCTCCGTGGACGTAGACAGCGACGGFTYTATAIQNVVHRCAGCACCGACCTGGTCCTCATCGGGGCCCCCCATTACTACGAGCAGACCCGAGGGGGCCAGGTGTCTGTGTGTCCCTTGCCCAGGGGLFHASYGARRDAAKGTGGAGAAGGTGGTGGTGTGATGCTGTTCTCTACGGGGAGCAGGGCCACCCCTGGGGTCGCTTTGGGGCGGCTCTGACAGTGCTGGGILIVITDGKKEGDSGGATGTGAATGGGGACAAGCTGACAGACGTGGTCATCGGGGCCCCAGGAGAGGAGGAGAACCGGGGTGCTGTCTACCTGTTTCACGGLDYKDVIPMADAAGAGTCTTGGGACCCAGCATCAGCCCCTCCCACAGCCAGCGGATCGCGGGCTCCCAGCTCTCCTCCAGGCTGCAGTATTTTGGGCAGGCIIRYAIGVGLAFQNACTGAGCGGGGGTCAAGACCTCACCCAGGATGGACTGGTGGACCTGGCTGTGGGGGCCCGGGGCCAGGTGCTCCTGCTCAGGACCAGRNSWKELNDIASKPACCTGTGCTCTGGGTGGGGGTGAGCATGCAGTTCATACCTGCCGAGATCCCCAGGTCTGCGTTTGAGTGTCGGGAGCAGGTGGTCTCSQEHIFKVEDFDALTGAGCAGACCCTGGTACAGTCCAACATCTGCCTTTACATTGACAAACGTTCTAAGAACCTGCTTGGGAGCCGTGACCTCCAAAGCTCKDIQNQLKEKIFAITGTGACCTTGGACCTGGCCCTCGACCCTGGCCGCCTGAGTCCCCGTGCCACCTTCCAGGAAACAAAGAACCGGAGTCTGAGCCGAGTEGTETTSSSSFELECCGAGTCCTCGGGCTGAAGGCACACTGTGAAAACTTCAACCTGCTGCTCCCGAGCTGCGTGGAGGACTCTGTGACCCCCATTACCTTMAQEGFSAVFTPDGGCGTCTGAACTTCACGCTGGTGGGCAAGCCCCTCCTTGCCTTCAGAAACCTGCGGCCTATGCTGGCCGCCGATGCTCAGAGATACTTPVLGAVGSFTWSGGCACGGCCTCCCTACCCTTTGAGAAGAACTGTGGAGCCGACCATATCTGCCAGGACAATCTCGGCATCTCCTTCAGCTTCCCAGGCTTAFLYPPNMSPTFINGAAGTCCCTGCTGGTGGGGAGTAACCTGGAGCTGAACGCAGAAGTGATGGTGTGGAATGACGGGGAAGACTCCTACGGAACCACCATMSQENVDMRDSYLGCACCTTCTCCCACCCCGCAGGACTGTCCTACCGCTACGTGGCAGAGGGCCAGAAACAAGGGCAGCTGCGTTCCCTGCACCTGACATGYSTELALWKGVQSLTGACAGCGCCCCAGTTGGGAGCCAGGGCACCTGGAGCACCAGCTGCAGAATCAACCACCTCATCTTCCGTGGCGGCGCCCAGATCACVLGAPRYQHTGKAVCTTCTTGGCTACCTTTGACGTCTCCCCCAAGGCTGTCCTGGGAGACCGGCTGCTTCTGACAGCCAATGTGAGCAGTGAGAACAACACIFTQVSRQWRMKATCCCAGGACCAGCAAGACCACCTTCCAGCTGGAGCTCCCGGTGAAGTATGCTGTCTACACTGTGGTTAGCAGCCACGAACAATTCACEVTGTQIGSYFGASCAAATACCTCAACTTCTCAGAGTCTGAGGAGAAGGAAAGCCATGTGGCCATGCACAGATACCAGGTCAATAACCTGGGACAGAGGGALCSVDVDSDGSTDLCCTGCCTGTCAGCATCAACTTCTGGGTGCCTGTGGAGCTGAACCAGGAGGCTGTGTGGATGGATGTGGAGGTCTCCCACCCCCAGAAVLIGAPHYYEQTRGCCCATCCCTTCGGTGCTCCTCAGAGAAAATCGCACCCCCAGCATCTGACTTCCTGGCGCACATTCAGAAGAATCCCGTGCTGGACTGGQVSVCPLPRGWRRCTCCATTGCTGGCTGCCTGCGGTTCCGCTGTGACGTCCCCTCCTTCAGCGTCCAGGAGGAGCTGGATTTCACCCTGAAGGGCAACCTWWCDAVLYGEQGHPCAGCTTTGGCTGGGTCCGCCAGATATTGCAGAAGAAGGTGTCGGTCGTGAGTGTGGCTGAAATTACGTTCGACACATCCGTGTACTCWGRFGAALTVLGDVCCAGCTTCCAGGACAGGAGGCATTTATGAGAGCTCAGACGACAACGGTGCTGGAGAAGTACAAGGTCCACAACCCCACCCCCCTCATNGDKLTDVVIGAPGCGTAGGCAGCTCCATTGGGGGTCTGTTGCTGCTGGCACTCATCACAGCGGTACTGTACAAAGTTGGCTTCTTCAAGCGTCAGTACAAEEENRGAVYLFHGVGGAAATGATGGAGGAGGCAAATGGACAAATTGCCCCAGAAAACGGGACACAGACCCCCAGCCCGCCCAGTGAGAAATGATCCCCTCTLGPSISPSHSQRIATTGCCTTGGACTTCTTCTCCCCCGCGAGTTTTCCCCACTTACTTACCCTCACCTGTCAGGCCTGACGGGGAGGAACCACTGCACCACGSQLSSRLQYFGQACGAGAGAGGCTGGGATGGGCCTGCTTCCTGTCTTTGGGAGAAAACGTCTTGCTTGGGAAGGGGCCTTTGTCTTGTCAAGGTTCCAACLSGGQDLTQDGLVDTGGAAACCCTTAGGACAGGGTCCCTGCTGTGTTCCCCAAAGGACTTGACTTGCAATTTCTACCTAGAAATACATGGACAATACCCCCLAVGARGQVLLLRTAGGCCTCAGTCTCCCTTCTCCCATGAGGCACGAATGATCTTTCTTTCCTTTCTTTTTTTTTTTTTTTCTTTTCTTTTTTTTTTTTTTRPVLWVGVSMQFIPGAGACGGAGTCTCGCTCTGTCACCCAGGCTGGAGTGCAATGGCGTGATCTCGGCTCACTGCAACCTCCGCCTCCCGGGTTCAAGTAAAEIPRSAFECREQVTTCTGCTGTCTCAGCCTCCTGAGTAGCTGGGACTACAGGCACACGCCACCTCGCCCGGCCCGATCTTTCTAAAATACAGTTCTGAATVSEQTLVQSNICLYATGCTGCTCATCCCCACCTGTCTTCAACAGCTCCCCATTACCCTCAGGACAATGTCTGAACTCTCCAGCTTCGCGTGAGAAGTCCCCIDKRSKNLLGSRDLTTCCATCCCAGAGGGTGGGCTTCAGGGCGCACAGCATGAGAGGCTCTGTGCCCCCATCACCCTCGTTTCCAGTGAATTAGTGTCATGQSSVTLDLALDPGRTCAGCATCAGCTCAGGGCTTCATCGTGGGGCTCTCAGTTCCGATTTCCCAGGCTGAATTGGGAGTGAGATGCCTGCATGCTGGGTTCLSPRATFQETKNRSTGCACAGCTGGCCTCCCGCGTTGGGCAACATTGCTGGCTGGAAGGGAGGAGCGCCCTCTAGGGAGGGACATGGCCCCGGTGCGGCTGLSRVRVLGLKAHCECAGCTCACCCAGCCCCAGGGGCAGAAGAGACCCAACCACTTCTATTTTTTGAGGCTATGAATATAGTACCTGAAAAAATGCCAAGACNFNLLLPSCVEDSVATGATTATTTTTTTAAAAAGCGTACTTTAAATGTTTGTGTTAATAAATTAAAACATGCACAAAAAGATGCATCTACCGCTCTTGGGATPITLRLNFTLVGK AATATGTCAAAGGTCTAAAAATAAAAAAGCCTTCTGTGAAAAAAAAAAAAAAAAAPLLAFRNLRPMLAA DAQRYFTASLPFEK NCGADHICQDNLG ISFSFPGLKSLLVGSNLELNAEVMVWND GEDSYGTTITFSHP AGLSYRYVAEGQKQ GQLRSLHLTCDSAPVGSQGTWSTSCRI NHLIFRGGAQITFL ATFDVSPKAVLGD RLLLTANVSSENNT PRTSKTTFQLELPVKYAVYTVVSSHEQF TKYLNFSESEEKES HVAMHRYQVNNLGQ RDLPVSINFWVPVELNQEAVWMDVEVSH PQNPSLRCSSEKIA PPASDFLAHIQKNP VLDCSIAGCLRFRCDVPSFSVQEELDFT LKGNLSFGWVRQIL QKKVSVVSVAEITF DTSVYSQLPGQEAFMRAQTTTVLEKYKV HNPTPLIVGSSIGG LLLLALITAVLYKV GFFKRQYKEMMEEANGQIAPENGTQTPS PPSEK SEQ ID NO.: 17 SEQ ID NO.: 64AATGGAGCCGCTGTCAGCAGAACCTTCTGCCGCCGCCGCCGCCGCCGCCGTCCCTCCTCTTTTTTTTCCCGGCAGATCTTTGTTGTGMVKFPALTHYWPLITGGGAGGGCAGCAGGGATGGACTTGAGCTTGCGGATCCCCTGCTAGAGCAGCCGCGCTCGGAGAAGGCGCCGCAGCCGCGAGGAGGARFLVPLGITNIAIDGCCGCCGCCGCCGCGCCCGAGGCCCCGCCGCCCGCGGCCTCTGTCGGCCCGCGCCCCGCTCGCCCCGTCGCCCCGTCGCCCCTCGCCFGEQALNRGIAAVKTCCCCGCAGAGTCCCCTCGCGGCAGCAGATGTGTGTGGGGTCAGCCCACGGCGGGGACTATGGTGAAATTCCCGGCGCTCACGCACTEDAVEMLASYGLAYACTGGCCCCTGATCCGGTTCTTGGTGCCCCTGGGCATCACCAACATAGCCATCGACTTCGGGGAGCAGGCCTTGAACCGGGGCATTGSLMKFFTGPMSDFKCTGCTGTCAAGGAGGATGCAGTCGAGATGCTGGCCAGCTACGGGCTGGCGTACTCCCTCATGAAGTTCTTCACGGGTCCCATGAGTGNVGLVFVNSKRDRTACTTCAAAAATGTGGGCCTGGTGTTTGTGAACAGCAAGAGAGACAGGACCAAAGCCGTCCTGTGTATGGTGGTGGCAGGGGCCATCGKAVLCMVVAGAIAACTGCCGTCTTTCACACACTGATAGCTTATAGTGATTTAGGATACTACATTATCAATAAACTGCACCATGTGGACGAGTCGGTGGGGAVFHTLIAYSDLGYYGCAAGACGAGAAGGGCCTTCCTGTACCTCGCCGCCTTTCCTTTCATGGACGCAATGGCATGGACCCATGCTGGCATTCTCTTAAAACIINKLHHVDESVGSACAAATACAGTTTCCTGGTGGGATGTGCCTCAATCTCAGATGTCATAGCTCAGGTTGTTTTTGTAGCCATTTTGCTTCACAGTCACCKTRRAFLYLAAFPFTGGAATGCCGGGAGCCCCTGCTCATCCCGATCCTCTCCTTGTACATGGGCGCACTTGTGCGCTGCACCACCCTGTGCCTGGGCTACTMDAMAWTHAGILLKACAAGAACATTCACGACATCATCCCTGACAGAAGTGGCCCGGAGCTGGGGGGAGATGCAACAATAAGAAAGATGCTGAGCTTCTGGTHKYSFLVGCASISDGGCCTTTGGCTCTAATTCTGGCCACACAGAGAATCAGTCGGCCTATTGTCAACCTCTTTGTTTCCCGGGACCTTGGTGGCAGTTCTGVIAQVVFVAILLHSCAGCCACAGAGGCAGTGGCGATTTTGACAGCCACATACCCTGTGGGTCACATGCCATACGGCTGGTTGACGGAAATCCGTGCTGTGTHLECREPLLIPILSATCCTGCTTTCGACAAGAATAACCCCAGCAACAAACTGGTGAGCACGAGCAACACAGTCACGGCAGCCCACATCAAGAAGTTCACCTLYMGALVRCTTLCLTCGTCTGCATGGCTCTGTCACTCACGCTCTGTTTCGTGATGTTTTGGACACCCAACGTGTCTGAGAAAATCTTGATAGACATCATCGGYYKNIHDIIPDRSGAGTGGACTTTGCCTTTGCAGAACTCTGTGTTGTTCCTTTGCGGATCTTCTCCTTCTTCCCAGTTCCAGTCACAGTGAGGGCGCATCGPELGGDATIRKMLTCACCGGGTGGCTGATGACACTGAAGAAAACCTTCGTCCTTGCCCCCAGCTCTGTGCTGCGGATCATCGTCCTCATCGCCAGCCTCGSFWWPLALILATQRTGGTCCTACCCTACCTGGGGGTGCACGGTGCGACCCTGGGCGTGGGCTCCCTCCTGGCGGGCTTTGTGGGAGAATCCACCATGGTCGISRPIVNLFVSRDLCCATCGCTGCGTGCTATGTCTACCGGAAGCAGAAAAAGAAGATGGAGAATGAGTCGGCCACGGAGGGGGAAGACTCTGCCATGACAGGGSSAATEAVAILTACATGCCTCCGACAGAGGAGGTGACAGACATCGTGGAAATGAGAGAGGAGAATGAATAAGGCACGGGACGCCATGGGCACTGCAGGGATYPVGHMPYGWLTACAGTCAGTCAGGATGACACTTCGGCATCATCTCTTCCCTCTCCCATCGTATTTTGTTCCCTTTTTTTTGTTTTGTTTTGGTAATGAEIRAVYPAFDKNNPAAGAGGCCTTGATTTAAAGGTTTCGTGTCAATTCTCTAGCATACTGGGTATGCTCACACTGACGGGGGGACCTAGTGAATGGTCTTTSNKLVSTSNTVTAAACTGTTGCTATGTAAAAACAAACGAAACAACTGACTTCATACCCCTGCCTCACGAAAACCCAAAAGACACAGCTGCCTCACGGTTGAHIKKFTFVCMALSLCGTTGTGTCCTCCTCCCCTGGACAATCTCCTCTTGGAACCAAAGGACTGCAGCTGTGCCATCGCGCCTCGGTCACCCTGCACAGCAGTLCFVMFWTPNVSEGCCACAGACTCTCCTGTCCCCCTTCATCGCTCTTAAGAATCAACAGGTTAAAACTCGGCTTCCTTTGATTTGCTTCCCAGTCACATGKILIDIIGVDFAFAGCCGTACAAAGAGATGGAGCCCCGGTGGCCTCTTAAATTTCCCTTCCGCCACGGAGTTCGAAACCATCTACTCCACACATGCAGGAGELCVVPLRIFSFFPGCGGGTGGCACGCTGCAGCCCGGAGTCCCCGTTCACACTGAGGAACGGAGACCTGTGACCACAGCAGGCTGACAGATGGACAGAATCVPVTVRAHLTGWLMTCCCGTAGAAAGGTTTGGTTTGAAATGCCCCGGGGGCAGCAAACTGACATGGTTGAATGATAGCATTTCACTCTGCGTTCTCCTAGATLKKTFVLAPSSVLTCTGAGCAAGCTGTCAGTTCTCACCCCCACCGTGTATATACATGAGCTAACTTTTTTAAATTGTCACAAAAGCGCATCTCCAGATTCRIIVLIASLVVLPYCAGACCCTGCCGCATGACTTTTCCTGAAGGCTTGCTTTTCCCTCGCCTTTCCTGAAGGTCGCATTAGAGCGAGTCACATGGAGCATCLGVHGATLGVGSLLCTAACTTTGCATTTTAGTTTTTACAGTGAACTGAAGCTTTAAGTCTCATCCAGCATTCTAATGCCAGGTTGCTGTAGGGTAACTTTTAGFVGESTMVAIAAGAAGTAGATATATTACCTGGTTCTGCTATCCTTAGTCATAACTCTGCGGTACAGGTAATTGAGAATGTACTACGGTACTTCCCTCCCCYVYRKQKKKMENEACACCATACGATAAAGCAAGACATTTTATAACGATACCAGAGTCACTATGTGGTCCTCCCTGAAATAACGCATTCGAAATCCATGCASATEGEDSAMTDMPGTGCAGTATATTTTTCTAAGTTTTGGAAAGCAGGTTTTTTCCTTTAAAAAAATTATAGACACGGTTCACTAAATTGATTTAGTCAGAPTEEVTDIVEMREEATTCCTAGACTGAAAGAACCTAAACAAAAAAATATTTTAAAGATATAAATATATGCTGTATATGTTATGTAATTTATTTTAGGCTATNEAATACATTTCCTATTTTCGCATTTTCAATAAAATGTCTCTAATACAATACGGTGATTGCTTGTGTGCTCAACATACCTGCAGTTGAAACGTATTGTATCAATGAACATTGTACCTTATTGGCAGCAGTTTTATAAAGTCCGTCATTTGCATTTGAATGTAAGGCTCAGTAAATGACAGAACTATTTTTCATTATGGGTAACTGGGGAATAAATGGGTCACTGGAGTAGGAATAGAAGTGCAAGCTGGAAAGGCAAAAATGAGAAAGAAAAAGGCAGGCCCTTTGTGTCTACCGTTTTCAGTGCTGTGTGATCATATTGTTCCTCACAGCAAAAAAGAATGCAAGGGCATAATGTTAGCTGTGAACATGCCAGGGTTGCATTCACATTCCTGGGTACCCAGTGCTGATGGGGTGTGCCCACGTGGGGACATGTCCTTGGCGTGCTTCCTCAGAGTGGCTTTTCCTCCATTAATACATATATGAGTACTGAAAAATTAAGTTGCATAGCTGCTTTGCAGTGGTTTCAGAGGCAGATCTGAGAAGATTAAAAAAAAATCTCAATGTATCAGCTTTTTTTAAAGGACATTACTAGAAAATTAAACAGTATTTTTTAACATGTGTGACTTTCATGCTTCTGGGGTTGGAGCTTAAAGATCCAAACTGAGAAAGCAGGCCGGGCATGGTGGCTCATGCCTGTAATCCCAACACTTTGGGAGGCCAAGGAGGGTGGATCACTTAAGGTCAGGAGTTTGAGACCAGCCTGGCCAACATGGCAAAACCCTGTCTCTACTAAAAACATAAAAATTAGCTGGGGGTGGTAGCACATACCTGTAATCCCAGCTACTCAGGAGGCTGAGGCAGGAGAATTTGCTTGATCCTGGGAGGCAGAGGTTGTAGTGAGCCGAGATCGCGCCATCGCACTCCAGCCTGGGTGACAAGAGCAAAACTCCATCTCSEQ ID NO.: 18 SEQ ID NO.: 65GACAGCCTCTGGGTCCTCGGTCGGTACAGTCTCTGCACCTCGCGCCCCAGCAGGTAAACTAACATTATGGATTTTTCCAAGCTACCCMDFSKLPKILDEDKAAAATACTCGATGAAGATAAAGAAAGCACATTTGGTTATGTGCATGGGGTCTCAGGACCTGTGGTTACAGCCTGTGACATGGCGGGTESTFGYVHGVSGPVGCAGCCATGTATGAGCTGGTGAGAGTGGGCCACAGCGAATTGGTTGGAGAGATTATTCGATTGGAGGGTGACATGGCTACTATTCAGVTACDMAGAAMYELGTGTATGAAGAAACTTCTGGTGTGTCTGTTGGAGATCCTGTACTTCGCACTGGTAAACCCCTCTCTGTAGAGCTTGGTCCTGGCATTVRVGHSELVGEIIRATGGGAGCCATTTTTGATGGTATTCAAAGACCTTTGTCGGATATCAGCAGTCAGACCCAAAGCATCTACATCCCCAGAGGAGTAAACLEGDMATIQVYEETGTGTCTGCTCTTAGCAGAGATATCAAATGGGACTTTACACCTTGCAAAAACCTACGGGTTGGTAGTCATATCACTGGCGGAGACATTSGVSVGDPVLRTGKTATGGAATTGTCAGTGAGAACTCGCTTATCAAACACAAAATCATGTTACCCCCACGAAACAGAGGAACTGTAACTTACATTGCTCCAPLSVELGPGIMGAICCTGGGAATTATGATACCTCTGATGTTGTCTTGGAGCTTGAATTTGAAGGTGTAAAGGAGAAGTTCACCATGGTGCAAGTATGGCCTFDGIQRPLSDISSQGTACGTCAAGTTCGACCTGTCACTGAGAAGCTGCCAGCCAATCATCCTCTGTTGACTGGCCAGAGAGTCCTTGATGCCCTTTTTCCGTQSIYIPRGVNVSATGTGTCCAGGGAGGAACTACTGCTATCCCTGGAGCCTTTGGCTGTGGAAAGACAGTGATATCACAGTCTCTATCCAAGTATTCTAACLSRDIKWDFTPCKNAGTGATGTAATCATCTATGTAGGATGTGGTGAAAGAGGAAATGAGATGTCTGAAGTCCTCCGGGACTTCCCAGAGCTCACAATGGAGLRVGSHITGGDIYGGTTGATGGTAAGGTAGAGTCAATTATGAAGAGGACAGCTTTGGTAGCCAATACCTCCAATATGCCTGTTGCTGCTAGAGAAGCCTCTIVSENSLIKHKIMLATTTATACTGGAATCACACTGTCAGAGTACTTCCGTGACATGGGCTATCATGTCAGTATGATGGCTGACTCTACCTCTAGATGGGCTPPRNRGTVTYIAPPGAGGCCCTTAGAGAAATCTCTGGTCGTTTAGCTGAAATGCCTGCAGATAGTGGATATCCAGCCTATCTTGGTGCCCGTCTGGCCTCGGNYDTSDVVLELEFTTTTATGAACGAGCAGGCAGGGTGAAATGTCTTGGAAATCCTGAAAGAGAAGGGAGTGTCAGCATTGTAGGAGCAGTTTCTCCACCTEGVKEKFTMVQVWPGGTGGTGATTTTTCTGATCCAGTTACATCTGCCACTCTTGGTATCGTTCAGGTGTTCTGGGGCTTAGATAAGAAACTAGCTCAACGTVRQVRPVTEKLPANAAGCATTTCCCCTCTGTCAATTGGCTCATCAGCTACAGCAAGTATATGCGTGCCTTGGATGAATACTATGACAAACACTTCACAGAGHPLLTGQRVLDALFTTCGTTCCTCTGAGGACGAAAGCTAAGGAAATTCTGCAGGAAGAAGAAGACCTGGCAGAAATTGTACAGCTTGTGGGAAAGGCTTCTPCVQGGTTAIPGAFTTGGCAGAAACAGATAAAATCACTCTGGAGGTAGCAAAACTTATCAAAGATGATTTCCTACAACAAAATGGATATACTCCTTATGACGCGKTVISQSLSKYAGGTTCTGCCCATTCTACAAGACAGTAGGGATGCTGTCCAACATGATTGCATTTTATGATATGGCTCGTAGAGCTGTTGAAACCACTSNSDVIIYVGCGERGCCCAGAGTGACAATAAAATCACATGGTCCATTATTCGTGAGCACATGGGAGACATCCTCTATAAACTTTCCTCCATGAAATTCAAGGNEMSEVLRDFPELGATCCACTGAAAGATGGTGAGGCAAAGATCAAAAGCGACTATGCACAACTTCTTGAAGACATGCAGAATGCATTCCGTAGCCTTGAATMEVDGKVESIMKRGATTAGAAGCCTTGAAGATTACAACTGTGATTTCCTTTTCCTCAGCAAGCTCCTATGTGTATATTTTCCTGAATTTCTCATCTCAAATALVANTSNMPVAACCCTTTGCTTCTTTATTGTGCAGCTTTGAGACTAGTGCCTATGTGTGTTATTTGTTTCCCTGTTTTTTTGGTAGGTCTTATATAAAAREASIYTGITLSEYCAAACATTCCTTTGTTCTAGTGTTGTGAAGGGCCTCCCTCTTCCTTTATCTGAAGTGGTGAATATAGTAAATATACATTCTGGTTACFRDMGYHVSMMADSACTACTGTAAACTTGTATGTAGGGTGATGACCCTCTTTGTCCTAGGTGTACCCTTTCCTCATCTCTATTAAATTGTAAACAGGACTATSRWAEALREISGRCTGCATGTACTCTCTTTGCAGTGAATTTGGAATGGAAGGCCAGGTTTCTATAACTTTTGAACAGGTACTTTGTGAAATGACTCAATTLAEMPADSGYPAYLTCTATTGTGGTAAGCTCATTGGCAGCTTAGCATTTTGCAAAGGAATTGCTTTGCAGGAAATATTTAATTTTCAAAAACATAATGATTGARLASFYERAGRVAATGTTCCAATTATGCATCACTTCCCCCAGTATAAATCAGGAATGTTTGTGAGAAACCATTGGGAACTATACTCTTTTTATTTTTATKCLGNPEREGSVSITTTTTATTTTTTTTATTATTTTTTTTTTGGGGACGGAGTGTCCCTCTTGTTGCCCAGGCTGGAGTGCAATGGCGTGATCTTGGCTCAVGAVSPPGGDFSDPCTGCAGCCTTCGCCTCCCGGGTTCAAGTGATTCTCCTGCCTCAGCCTCCCGAGTAGCTGGGATTACAGGCATGCTCCACCATGCCCAVTSATLGIVQVFWGGCTAATTTTGTATTTTTAGTAGAAACGGGGTTTCACCATATTGGTCAGGCTGGTCTCGAACTCCAGACCTCAGGTGATCCGCCCACCLDKKLAQRKHFPSVTCGGCCTCCCAAACTGCTGGGATTACAGGCGTGAGCCACCGCGCCTGGCCAGGGACTATACTCTTTTTAAAATAGACATTTGTGGGGNWLISYSKYMRALDCTCACACAATATATGAAATAGTACCCTCTAAAAAAGAGAAAAAAAAAATCAGGCGGTCAAACTTAGAGCAACATTGTCTTATTAAAGEYYDKHFTEFVPLRCATAGTTTATTTCACTAGAAAAAATTTAATATCAAGGACTATTACATACTTCATTACTAGGAAGTTCTTTTTAAAATGACACTTAAATKAKEILQEEEDLAACAATCACTGAAAACTTGATCCACATCACACCCTGTTTATTTTCCTTAAACATCTTGGAAGCCTAAGCTTCTGAGAATCATGTGGCAEIVQLVGKASLAETAGTGTGATGGGCAGTAAAATACCAGAGAAGATGTTTAGTAGCAATTAAAGGCTGTTTGCACCTTTAAGGACCAGCTGGGCTGTAGTGDKITLEVAKLIKDDATTCCTGGGGCCAGAGTGGCATTATGTTTTTACAAAATAATGACATATGTCACATGTTTGCATGTTTGTTTGCTTGTTGAATTTTTGFLQQNGYTPYDRFCAACAGCCAGTTGACCAATCATAGAAAGTATTACTTTCTTTCATATGGTTTTTGGTTCACTGGCTTAAGAGGTTTCTCAGAATATCTAPFYKTVGMLSNMIATGGCCACAGCAGCATACCAGTTTCCATCCTAATAGGAATGAAATTAATTTTGTATCTACTGATAACAGAATCTGGGTCACATGAAAAFYDMARRAVETTAQAAAATCATTTTATCCGTCTTTTAAGTATATGTTTAAAATAATAATTTATGTGTCTGCATATTGCAGAACAGCTCTGAGAGCAACAGTSDNKITWSIIREHMTTCCCATTAACTCTTTCTGACCAATAGTGCTGGCACCGTTGCTTCCTCTTTGGGAAGAGGAAAGGGTGTGTGAACATGGCTAACAATGDILYKLSSMKFKDCTTCAAATACCCAAATTGTGATAGCATAAATAAAGTATTTATTTTATGCCTCAGTATATTATTATTTAATTTTTTAGGTAATGCCTAPLKDGEAKIKSDYATCTCTTGGTCTATTAAGGAAAGAAGCAATCAGTAGAGAATTCAGGATAGTTTTGTTTAAATTCTTGCAGATTACATGTTTTTACAGTQLLEDMQNAFRSLEGGCCTGCTATTGAGGAAAGGTATTCTTCTATACAACTTGTTTTAACCTTTGAGAACATTGACAGAAATTATGCAATGGTTTGTTGAGDATACGGACTTGATGGTGCTGTTTAATCAGTTTGCTTCCAAAGTGGCCTACTCAAGAGGCCCTAAGACTGGTAGAAATTAAAAGGATTTCAAAAACTTTCTATTCCTTTCTTAAACCTACCAGCAAACTAGGATTGTGATAGCAATGAATGGTATGATGAAGAAAGTTTGACCAAATTTGTTTTTTTGTTGTTGTTGTTGTTTTGAATTTGAAATCATTCTTATTCCCTTTAAGAATGTTTATGTATGAGTGTGAAGATGCTAGCGAACCTATGCTCAGATATTCATCGTAAGTCTCCCTTCACCTGTTACAGAGTTTCAGATCGGTCACTGATAGTATGTATTTCTTTAGTAAGAATGTGTTAAAATTACAATGATCTTTTAAAAAGATGATGCAGTTCTGTATTTATTGTGCTGTGTCTGGTCCTAAGTGGAGCCAATTAAACAAGTTTCATATGTATTTTTCCAGTGTTGAATCTCACACACTGTACTTTGAAAATTTCCTTCCATCCTGAATAACGAATAGAAGAGGCCATATATATTGCCTCCTTATCCTTGAGATTTCACTACCTTTATGTTAAAAGTTGTGTATAATTGTTAAAATCTGTGAAAGAATAAAAAGTGGATTTAAATTAAAAAAAAAAAAAAAAAAAA SEQ ID NO.: 19 SEQ ID NO.:66ACGCCTGGTCTCTGGGACGCCCCTCCGGACCCGTTTCGCCTCGCGGAGCCGGTAGGTCCAGGTGCAGCGGCCGCAGTGCTGCGTCCGMIRQERSTSYQELSTGCGCCGCGGGCTGGGGCGGTCTCAGGTGTGCCGAAGCTCTGGTCAGTGCCATGATCCGGCAGGAGCGCTCCACATCCTACCAGGAGEELVQVVESSELADCTGAGTGAGGAGTTGGTCCAGGTGGTTGAGAGCTCAGAGCTGGCAGACGAGCAGGACAAGGAGACGGTCAGAGTCCAAGGTCCGGGTEQDKETVRVQGPGIATCTTACCAGGCCTGGACAGCGAGTCCGCCTCCAGCAGCATCCGCTTCAGCAAGGCCTGCCTGAAGAACGTCTTCTCGGTCCTACTCLPGLDSESASSSIRATCTTCATCTACCTGCTGCTCATGGCTGTGGCCGTCTTCCTGGTCTACCGGACCATCACAGACTTTCGTGAGAAACTCAAGCACCCTFSKACLKNVFSVLLGTCATGTCTGTGTCTTACAAGGAAGTGGATCGCTATGATGCCCCAGGTATTGCCTTGTACCCCGGTCAGGCCCAGTTGCTCAGCTGTIFIYLLLMAVAVFLAAGCACCATTACGAGGTCATTCCTCCTCTGACAAGCCCTGGCCAGCCGGGTGACATGAATTGCACCACCCAGAGGATCAACTACACGVYRTITDFREKLKHGACCCCTTCTCCAATCAGACTGTGAAATCTGCCCTGATTGTCCAGGGGCCCCGGGAAGTGAAAAAGCGGGAGCTGGTCTTCCTCCAGPVMSVSYKEVDRYDTTCCGCCTGAACAAGAGTAGTGAGGACTTCAGCGCCATTGATTACCTCCTCTTCTCTTCTTTCCAGGAGTTCCTGCAAAGCCCAAACAPGIALYPGQAQLLAGGGTAGGCTTCATGCAGGCCTGTGAGAGTGCCTGTTCCAGCTGGAAGTTCTCTGGGGGCTTCCGCACCTGGGTCAAGATGTCACTGSCKHHYEVIPPLTSGTAAAGACCAAGGAGGAGGATGGGCGGGAAGCAGTGGAGTTCCGGCAGGAGACAAGTGTGGTTAACTACATTGACCAGAGGCCAGCTPGQPGDMNCTTQRIGCCAAAAAAAGTGCTCAATTGTTTTTTGTGGTCTTTGAATGGAAAGATCCTTTCATCCAGAAAGTCCAAGATATAGTCACTGCCAATNYTDPFSNQTVKSACCTTGGAACACAATTGCTCTTCTCTGTGGCGCCTTCTTGGCATTATTTAAAGCAGCAGAGTTTGCCAAACTGAGTATAAAATGGATGLIVQGPREVKKRELATCAAAATTAGAAAGAGATACCTTAAAAGAAGAGGTCAGGCAACGAGCCACATAAGCTGAAGTCACCTCGCGTTGTTTAGAGAACTGVFLQFRLNKSSEDFTCCACATCAATGGGAGCTGTCATCACTTCCACTTTGTAAACGGAGCTATCAACAATCCTGTACTCACTTGAAGAAATGGGGCCTTGCSAIDYLLFSSFQEFTGGGAGGAACAGCATGTAAAACTGGAACTTCTAACCCCGTCCCAAAAGAGGCGGTGTAGAGCCTAATAGAAGAGACTAATGGATAAALQSPNRVGFMQACECCTACAAGTTATTTAAATATTTAAATTATTAATAAACTTTTTAAAGAGCTGGCCAATGACTTTTGAATAGGGTTTGTAGAAGATGCCSACSSWKFSGGFRTTTTCTTCCTGTTTGGTTCATTGTATTGTATTAGGTTAAGCTCTACTAGGGTAATGAAGGCTCTACTTTTCACTTTTTAAAAGTGGACWVKMSLVKTKEEDGAAAAGAGTGTGATTTTCTTTTTCCAAAAATTCCTGAGTATCAAGACGTGCAGGTCATGCTTTGGAGCCTATGCACTGTACACAATGGREAVEFRQETSVVNCAAAACCCTATGACTTTGGCATCATCTGCCATTGATGTCCAGCCTCTGACATGCTCTTTGATTTGTTAAATGTTAAATGAGACTTTAYIDQRPAAKKSAQLAGGCTACTAGAAACTAGTAATTAAGTTTCTTAATGGACTGAGTAGCCACCTACTTGTCCGGCTAGAATGTTTGTTGATGTATGAGTTFFVVFEWKDPFIQKTAGATTAACACTCAAAAGCACTAGGACAGATGTACATAGAAGGTGCCTACTCATTGTATTTTGATGATTTCATTAACAGGTAAATAAVQDIVTANPWNTIAAAGTTAATACAAAAGGAACGAGTGTGACAATATGAATATCTGCTCAATCATCGGGCACAATTACTTTCATTTGGTGACTTCCAAGGALLCGAFLALFKAAECAAAAAGGTAGTATGAGTCTGGACTCCCAAGATGGATCTAACTCTCAAGGTATGTTCTAACTGCTTCCAGGGAAGGGTTTGTTAGGCFAKLSIKWMIKIRKATGGCAACTGATGGCAGGTGTCCAGAAAGAGTGACCTGGTGTCCCCGAGGAAGCTGGGTTAACTCTTTACTGTGTCCACAAAACTACRYLKRRGQATSHISCCATCATATGAGGAAGGGGTATACGCAGTGTGACCCTCAAAAAGCTTTTAGCCTAGCCTTTGACAGAAATGAGTATGCATTAAAAAAAAGTCTATTTTTCACATTAAGGTTCTAAAAATTGTTTCCAGAGTTTTAAATTATTTATGTGCCTGTTGCTTCAAAGAGGACTTGGTAGCATTTCCTAAATTTTGTAATCTGGCTTCCGATAATCCAAAGGGAATAACTCAAATGTATGAATAGGCATTTTAAATGGGAAGAAACTGTTTTTTGGATGAATGATTAAAAGTGAACTGTATAAAG SEQ ID NO.: 20 SEQ ID NO.: 67GCGGACGTGGGCAGGAGGGCTGGAAAAGCCGGCGCTGGAGCGGGAACGGGAGTAGCTGCCTGGGCGCCAAAGGCCGCGGCACTCCCAMFRKGKKRHSSSSSCGCGGACCCCGAAGTCCGCAACCCGGGGATGGGCCCGCGGCTGCGAGGGGATCTTCTCTGGATCAAGCAATGGTGGTGAAAAATGTTQSSEISTKSKSVDSTCGCAAGGGCAAAAAACGACACAGTAGTAGCAGTTCCCAAAGTAGCGAAATCAGTACTAAGAGCAAGTCTGTGGATTCTAGCCTTGGSLGGLSRSSTVASLGGGTCTTTCACGATCCAGCACTGTGGCCAGCCTCGACACAGATTCCACCAAAAGCTCAGGACAAAGCAACAATAATTCAGATACCTGDTDSTKSSGQSNNNTGCAGAATTTCGAATAAAATATGTTGGTGCCATTGAGAAACTGAAACTCTCCGAGGGAAAAGGCCTTGAAGGGCCATTAGACCTGATSDTCAEFRIKYVGAAAATTATATAGACGTTGCCCAGCAAGATGGAAAGTTGCCTTTTGTTCCTCCGGAGGAAGAATTTATTATGGGAGTTTCCAAGTATGGIEKLKLSEGKGLEGCATAAAAGTATCAACATCAGATCAATATGATGTTTTGCACAGGCATGCTCTCTACTTAATAATCCGGATGGTGTGTTACGATGACGGPLDLINYIDVAQQDTCTGGGGGCGGGAAAAAGCTTACTGGCTCTGAAGACCACAGATGCAAGCAATGAGGAATACAGCCTGTGGGTTTATCAGTGCAACAGGKLPFVPPEEEFIMCCTGGAACAAGCACAAGCCATTTGCAAGGTTTTATCCACCGCTTTTGACTCTGTATTAACATCTGAGAAACCCTGAATCCTGCAATCGVSKYGIKVSTSDQAAGTAGAAGTCAACTTCATCTGAAAGTTCAGCTGTTTTCAAACTGCAATGCTGAAATGTTATGCAAATAATGAAGTTATCCCTTGCTYDVLHRHALYLIIRCTAGATTTTCTGAAGAAAATGGATTGTGTAAAATGCTGATCATTTGTTTATTAAAATGTGTCCTATTACACAGTGAGTTAACTCTCAMVCYDDGLGAGKSLATGAAGTCATCTATTTTCTGGGCTAAAAAACTTCATTTGTCTTTTTCAACTTCTAATAAGCTTAACCTAAGTGTCACGAAGACGAGALALKTTDASNEEYSTGTCACAGAGGTCCACTCAGTGACAAACACACACTGAAGGCCTGAGGGAAGACTGAGGACATGGGCTCAGTGGTGGCTTCCCAGTCALWVYQCNSLEQAQATGGTATCACTGGCATGGACCTCTGTCCGGCAGAGGTGTGGACTGGAGACCAGGATTCATGCTGGTCTGGAACAATGACATTGCCAACICKVLSTAFDSVLTTTAAGACACACAAAGCAGATTTTCAGAAGTGTCTGGTCAAGATAACATGCTGGCCAACCACAATTCCTAGAGTTAAGAGAACCTTAASEKPAAGATTACCGCTCATGCTAAAAGTATGTAAAGATCCCATGTACAGTATGATAGTGTACTTTTTTTAAAGGACTGTCAATATACAAAACTTTAAAGATTAAAAACATTAAAAATAAAAAAA SEQ ID NO.: 21 SEQ ID NO.: 68CCTCGCCCCGCCTACGCGGGAACCCAACCGCGGCGACCGGACGTGCACTCCTCCAGTAGCGGCTGCACGTCGTGCAATGGCCCGCTAMARYEEVSVSGFEETGAGGAGGTGAGCGTGTCCGGCTTCGAGGAGTTCCACCGGGCCGTGGAACAGCACAATGGCAAGACCATTTTCGCCTACTTTACGGGFHRAVEQHNGKTIFTTCTAAGGACGCCGGGGGGAAAAGCTGGTGCCCCGACTGCGTGCAGGCTGAACCAGTCGTACGAGAGGGGCTGAAGCACATTAGTGAAYFTGSKDAGGKSWAGGATGTGTGTTCATCTACTGCCAAGTAGGAGAAAAGCCTTATTGGAAAGATCCAAATAATGACTTCAGAAAAAACTTGAAAGTAACCPDCVQAEPVVREGAGCAGTGCCTACACTACTTAAGTATGGAACACCTCAAAAACTGGTAGAATCTGAGTGTCTTCAGGCCAACCTGGTGGAAATGTTGTTLKHISEGCVFIYCQCTCTGAAGATTAAGATTTTAGGATGGCAATCATGTCTTGATGTCCTGATTTGTTCTAGTATCAATAAACTGTATACTTGCTTTGAATVGEKPYWKDPNNDFTCATGTTAGCAATAAATGATGTTAAAAAAACTGGCATGTGTCTAAACAATAGAGTGCTATTAAAATGCCCATGAACCTTTAGTTTGCRKNLKVTAVPTLLKCTGTAATACATGGATATTTTTAAGATATAAAGAAGTCTTCAGAAATAGCAGTAAAGGCTCAAAGGAACGTGATTCTTGAAGGTGACGYGTPQKLVESECLQ GTAATACCTAAAAACTCCTAAAGGTGCAGAGC ANLVEMLFSED SEQ ID NO.:22 SEQ ID NO.: 69TCGGAGCTGAACTTCCTAAAAGACAAAGTGTTTATCTTTCAAGATTCATTCTCCCTGAATCTTACCAACAAAACACTCCTGAGGAGAMNSSKSSETQCTERAAGAAAGAGAGGGAGGGAGAGAAAAAGAGAGAGAGAGAAACAAAAAACCAAAGAGAGAGAAAAAATGAATTCATCTAAATCATCTGAGCFSSQMFLWTVAGAACACAATGCACAGAGAGAGGATGCTTCTCTTCCCAAATGTTCTTATGGACTGTTGCTGGGATCCCCATCCTATTTCTCAGTGCCTGIPILFLSACFITRCTTTCATCACCAGATGTGTTGTGACATTTCGCATCTTTCAAACCTGTGATGAGAAAAAGTTTCAGCTACCTGAGAATTTCACAGAGCTVVTFRIFQTCDEKKCTCCTGCTACAATTATGGATCAGGTTCAGTCAAGAATTGTTGTCCATTGAACTGGGAATATTTTCAATCCAGCTGCTACTTCTTTTCFQLPENFTELSCYNTACTGACACCATTTCCTGGGCGTTAAGTTTAAAGAACTGCTCAGCCATGGGGGCTCACCTGGTGGTTATCAACTCACAGGAGGAGCAYGSGSVKNCCPLNWGGAATTCCTTTCCTACAAGAAACCTAAAATGAGAGAGTTTTTTATTGGACTGTCAGACCAGGTTGTCGAGGGTCAGTGGCAATGGGTEYFQSSCYFFSTDTGGACGGCACACCTTTGACAAAGTCTCTGAGCTTCTGGGATGTAGGGGAGCCCAACAACATAGCTACCCTGGAGGACTGTGCCACCATISWALSLKNCSAMGGAGAGACTCTTCAAACCCAAGGCAAAATTGGAATGATGTAACCTGTTTCCTCAATTATTTTCGGATTTGTGAAATGGTAGGAATAAAAHLVVINSQEEQEFTCCTTTGAACAAAGGAAAATCTCTTTAAGAACAGAAGGCACAACTCAAATGTGTAAAGAAGGAAGAGCAAGAACATGGCCACACCCALSYKKPKMREFFIGCCGCCCCACACGAGAAATTTGTGCGCTGAACTTCAAAGGACTTCATAAGTATTTGTTACTCTGATATAAATAAAAATAAGTAGTTTTLSDQVVEGQWQWVDAAATGTTATAATTCATGTTACTGGCTGAAGTGCATTTTCTCTCTACGTTAGTCTCAGGTCCTCTTCCCAGAATTTACAAAGCAATTCGTPLTKSLSFWDVGATACCTTTTGCTACATTTGCCTCATTTTTTAGTGTTCGTATGAAAGTACAGGGACACGGAGCCAAGACAGAGTCTAGCAAAGAAGGGEPNNIATLEDCATMGATTTTGGAAGGTGCCTTCCAAAAATCTCCTGAATCCGGGCTCTGTAGCAGGTCCTCTTCTTTCTAGCTTCTGACAAGTCTGTCTTCRDSSNPRQNWNDVTTCTTCTTGGTTTCATACCGTTCTTATCTCCTGCCCAAGCATATATCGTCTCTTTACTCCCCTGTATAATGAGTAAGAAGCTTCTTCACFLNYFRICEMVGIAGTCATGAAACTTATTCCTGCTCAGAATACCGGTGTGGCCTTTCTGGCTACAGGCCTCCACTGCACCTTCTTAGGGAAGGGCATGCCNPLNKGKSLAGCCATCAGCTCCAAACAGGCTGTAACCAAGTCCACCCATCCCTGGGGCTTCCTTTGCTCTGCCTTATTTTCAATTGACTGAATGGATCTCACCAGATTTTGTATCTATTGCTCAGCTAGGACCCGAGTCCAATAGTCAATTTATTCTAAGCGAACATTCATCTCCACACTTTCCTGTCTCAAGCCCATCCATTATTTCTTAACTTTTATTTTAGCTTTCGGGGGTACATGTTAAAGGCTTTTTATATAGGTAAACTCATGTCGTGGAGGTTTGTTGTACAGATTATTTCATCACCCAGGTATTAAGCCCAGTGCCTAATATTGTTTTTTTCGGCTCCTCTCCCTCCTCCTACCTTCCGCCCTCAAGTAGACTCCAGTGTCTGTTATTCCCTTCTTTGTGTTTATGAATTCTCATCATTTAGCTCCCACTTATAAGTGAGGACATGCAGTATTTGGTTTTCTGTTCCCATGTTTGCTAAGGATAATGGTTTCCAGTTCTACCGATGTTCCCACAAAAGACATAATTTTCTTTTTTAAGGCTGCTTAGTATTCCATGGTATCTATGTATCACATTTTCTCTATCCAATCTATTGTTGACTCACATTTAGATTGATTCCATGTTTTTGCTATTGTGAATAGTGCTGCAATGAACATTCGTGTGCATGTGTCTTTATGGTAGAAAGATTTATATTTCTCTGAGTATGTATCCAGTAATAGCCCATTCATTTATTGCATAAAATTCTACCAATAC SEQ ID NO.: 23SEQ ID NO.: 70CCTCCTCTCCCTGGCTTTTGTGTTGGTGCCTCCGAGCTGCAAGGAGGGTGCGCTGGAGGAGGAGGAGGGGGGCCCGGAGTGAGAGGCMAQPILGHGSLQPAACCCCCTTCACGCGCGCGCGCGCACACGGTGCCGGCGCACGCACACACGGGCGGACACACACACACGCGCGCACACACACACGCACASAAGLASLELDSSLGAGCTCGCTCGCCTCGAGCGCACGAACGTGGACGTTCTCTTTGTGTGGAGCCCTCAAGGGGGGTTGGGGCCCCGGTTCGGTCCGGGGDQYVQIRIFKIIVIGAGATGGCGCAGCCCATCCTGGGCCATGGGAGCCTGCAGCCCGCCTCGGCCGCTGGCCTGGCGTCCCTGGAGCTCGACTCGTCGCTGGDSNVGKTCLTFRFGACCAGTACGTGCAGATTCGCATCTTCAAAATAATCGTGATTGGGGACTCCAACGTGGGCAAGACCTGCCTGACCTTCCGCTTCTGCCGGTFPDKTEATIGGGGGGTACCTTCCCAGACAAGACTGAAGCCACCATCGGCGTGGACTTCAGGGAGAAGACCGTGGAAATCGAGGGCGAGAAGATCAAGVDFREKTVEIEGEKGTTCAGGTGTGGGACACAGCAGGTCAGGAACGTTTCCGCAAAAGCATGGTCGAGCATTACTACCGCAACGTACATGCCGTGGTCTTCIKVQVWDTAGQERFGTCTATGACGTCACCAAGATGACATCTTTCACCAACCTCAAAATGTGGATCCAAGAATGCAATGGGCATGCTGTGCCCCCACTAGTCRKSMVEHYYRNVHACCCAAAGTGCTTGTGGGCAACAAGTGTGACTTGAGGGAACAGATCCAGGTGCCCTCCAACTTAGCCCTGAAATTTGCTGATGCCCACVVFVYDVTKMTSFTAACATGCTCTTGTTTGAGACATCGGCCAAGGACCCCAAAGAGAGCCAGAACGTGGAGTCGATTTTCATGTGCTTGGCTTGCCGATTGNLKMWIQECNGHAVAAGGCCCAGAAATCCCTGCTGTATCGTGATGCTGAGAGGCAGCAGGGGAAGGTGCAGAAACTGGAGTTCCCACAGGAAGCTAACAGTPPLVPKVLVGNKCDAAAACTTCCTGTCCTTGTTGAAACCAAACGATATAAATACAAGATAAATTATCACTGGAGTTTTTTCTTTCCCTTTTTTCTGTGCCTLREQIQVPSNLALKGCATAATGCTGACACCTGCTTGTTTCCATACAAATTGATATCAAAATAAAATTTGTATAGATTAAAAAAAAAAAAAAAAAAAAAFADAHNMLLFETSA KDPKESQNVESIFM CLACRLKAQKSLLY RDAERQQGKVQKLEFPQEANSKTSCPC SEQ ID NO.: 24 SEQ ID NO.: 71GGAGCGCGTGAGGCTCCGGCGCGCAAGCCCGGAGCAGCCCGCTGGGGCGCACAGGGTCGCGCGGGCGCGGGGATGGAGGACGGCGTGMEDGVAGPQLGAAAGCCGGTCCCCAGCTCGGGGCCGCGGCGGAGGCGGCGGAGGCGGCCGAGGCGCGAGCGCGGCCCGGGGTGACGCTGCGGCCCTTCGCGEAAEAAEARARPGVCCCCTCTCGGGGGCGGCCGAGGCGGACGAGGGCGGCGGCGACTGGAGCTTCATTGACTGCGAGATGGAGGAGGTGGACCTGCAGGACTLRPFAPLSGAAEACTGCCCAGCGCCACCATCGCCTGTCACCTGGACCCGCGCGTGTTCGTGGACGGCCTGTGCCGGGCCAAATTTGAGTCCCTCTTTAGGDEGGGDWSFIDCEMACGTATGACAAGGACATCACCTTTCAGTATTTTAAGAGCTTCAAACGAGTCAGAATAAACTTCAGCAACCCCTTCTCCGCAGCAGATEEVDLQDLPSATIAGCCAGGCTCCAGCTGCATAAGACTGAGTTTCTGGGAAAGGAAATGAAGTTATATTTTGCTCAGACCTTACACATAGGAAGCTCACACCHLDPRVFVDGLCRCTGGCTCCGCCAAATCCAGACAAGCAGTTTCTGATCTCCCCTCCCGCCTCTCCGCCAGTGGGATGGAAACAAGTGGAAGATGCGACCAKFESLFRTYDKDICCAGTCATAAACTATGATCTCTTATATGCCATCTCCAAGCTGGGGCCAGGGGAAAAGTATGAATTGCACGCAGCGACTGACACCACTTFQYFKSFKRVRINCCCAGCGTGGTGGTCCATGTATGTGAGAGTGATCAAGAGAAGGAGGAAGAAGAGGAAATGGAAAGAATGAGGAGACCTAAGCCAAAAFSNPFSAADARLQLATTATCCAGACCAGGAGGCCGGAGTACACGCCGATCCACCTCAGCTGAACTGGCACGCGACGAGGACGCATTCCAAATCATACTCACHKTEFLGKEMKLYFGGGAGGAATCTTTTACTGTGGAGGTGGCTGGTCACGACTTCTTCGGAGGTGGCAGCCGAGATCGGGGTGGCAGAAATCCCAGTTCATAQTLHIGSSHLAPPGTTGCTCAGAAGAGAATCAAGGCCGTGTCCCCTTGTTCTAATGCTGCACACCAGTTACTGTTCATGGCACCCGGGAATGACTTGGGCNPDKQFLISPPASPCAATCACTGAGTTTGTGGTGATCGCACAAGGACATTTGGGACTGTCTTGAGAAAACAGATAATGATAGTGTTTTGTACTTGTTCTTTPVGWKQVEDATPVITCTGGTAGGTTCTGTCTGTGCCAAGGGCAGGTTGATCAGTGAGCTCAGGAGAGAGCTTCCTGTTTCTAAGTGGCCTGCAGGGGCCACNYDLLYAISKLGPGTCTCTACTGGTAGGAAGAGGTACCACAGGAAGCCGCCTAGTGCAGAGAGGTTGTGAAAACAGCAGCAATGCAATGTGGAAATTGTAGEKYELHAATDTTPSCGTTTCCTTTCTTCCCTCATGTTCTCATGTTTGTGCATGTATATTACTGATTTACAAGACTAACCTTTGTTCGTATATAAAGTTACAVVVHVCESDQEKEECCGTTGTTGTTTTACATCTTTTGGGAAGCCAGGAAAGCGTTTGGAAAACGTATCACCTTTCCCAGATTCTCGGATTCTCGACTCTTTEEEMERMRRPKPKIGCAACAGCACTTGCTTGCGGAACTCTTCCTGGAATGCATTCACTCAGCATCCCCAACCGTGCAACGTGTAACTTGTGCTTTTGCAAAIQTRRPEYTPIHLSAGAAGTTGATCTGAAATTCCTCTGTAGAATTTAGCTTATACAATTCAGAGAATAGCAGTTTCACTGCCAACTTTTAGTGGGTGAGAAATTTTAGTTTAGGTGTTTGGGATCGGACCTCAGTTTCTGTTGTTTCTTTTATGTGGTGGTTTCTATACATGAATCATAGCCAAAAACTTTTTTGGAAACTGTTGGTTGAGATAGTTGGTTCTTTTACCCCACGAAGACATCAAGATACACTTGTAAATAAAGCTGATAGCATATATTCATACCTGTTGTACACTTGGGTGAAAAGTATGGCAGTGGGAGACTAAGATGTATTAACCTACCTGTGAATCATATGTTGTAGGAAAAGCTGTTCCCATGTCTAACAGGACTTGAATTCAAAGCATGTCAAGTGGATAGTAGATCTGTGGCGATATGAGAGGGATGCAGTGCCTTTCCCCATTCATTCCTGATGGAATTGTTATACTAGGTTAACATTTGTAATTTTTTTCTAGTTGTAATGTGTATGTCTGGTAAATAGGTATTATATTTTGGCCTTACAATACCGTAACAATGTTTGTCATTTTGAAATACTTAATGCCAAGTAACAATGCATGCTTTGGAAATTTGGAAGATGGTTTTATTCTTTGAGAAGCAAATATGTTTGCATTAAATGCTTTGATTGTTCATATCAAGAAATTGATTGAACGTTCTCAAACCCTGTTTACGGTACTTGGTAAGAGGGAGCCGGTTTGGGAGAGACCATTGCATCGCTGTCCAAGTGTTTCTTGTTAAGTGCTTTTAAACTGGAGAGGCTAACCTCAAAATATTTTTTTTAACTGCATTCTATAATAAATGGGCACAGTATGCTCCTTACAGAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA SEQ ID NO.: 25 SEQ ID NO.: 72GATTGCGAGCCAGGAGGAGGAAGCCGGCGGTGGCCCCGTCAGCAGCCGGCTGCTGAGAGGCCGGTAGGCGGCGGCGGTCCCGAGGGGMKLYSLSVLYKGEACGGCGGCCGCGCTGCTCCCTGAGAACGGGTCCCGCAGCTGGGCAGGCGGGCGGCCTGAGGGCGCGGAGCCATGAAGCTGTACAGCCTKVVLLKAAYDVSSFCAGCGTCCTCTACAAAGGCGAGGCCAAGGTGGTGCTGCTCAAAGCCGCATACGATGTGTCTTCCTTCAGCTTTTTCCAGAGATCCAGSFFQRSSVQEFMTFCGTTCAGGAATTCATGACCTTCACGAGTCAACTGATTGTGGAGCGCTCATCGAAAGGCACTAGAGCTTCTGTCAAAGAACAAGACTATSQLIVERSSKGTRTCTGTGCCACGTCTACGTCCGGAATGATAGTCTTGCAGGTGTGGTCATTGCTGACAATGAATACCCATCCCGGGTGGCCTTTACCTTASVKEQDYLCHVYVGCTGGAGAAGGTACTAGATGAATTCTCCAAGCAAGTCGACAGGATAGACTGGCCAGTAGGATCCCCTGCTACAATCCATTACCCAGCRNDSLAGVVIADNECCTGGATGGTCACCTCAGTAGATACCAGAACCCACGAGAAGCTGATCCCATGACTAAAGTGCAGGCCGAACTAGATGAGACCAAAATYPSRVAFTLLEKVLCATTCTGCACAACACCATGGAGTCTCTGTTAGAGCGAGGTGAGAAGCTAGATGACTTGGTGTCCAAATCCGAGGTGCTGGGAACACADEFSKQVDRIDWPVGTCTAAAGCCTTCTATAAAACTGCCCGGAAACAAAACTCATGCTGTGCCATCATGTGATGCAGCCTGCCAGAGGCCCAATGCTGGAAGSPATIHYPALDGHTGGCACCATCATTCACATCAGAACTGCAGCCCCTGGAAAAGAAGAGACAGCCATAGACGAGGAGCCAGAGTGGGGGCAGACTGGCCALSRYQNPREADPMTTTTTTATTTTGAAGTTCCTGCGAGAAATGGATGGTGGAAGGGTGGCGAATGTTCAAATTCATATGTGTGGTAGTGATTCTTGGAAAGKVQAELDETKIILHAATTTGAGGTCCCCAAAGGTGTATTTTTGGGCAAATGAAACCATAAACTCCGACTGGCTTCTGTAGATGCCAAAGGGCTCTTTTTCANTMESLLERGEKLDGCTAACCCTGGGAAGGCTCTGTGGGAGGGAGGTCGGAGCCAGCTGTTTCTCGATCTTTGGTATATCTTTGGATCTTATTTGTACATTDLVSKSEVLGTQSKAATGATATTAACACTCCAGTGGGGGGTGGGGAGTCCCTGATGCTAGGGCTGGGGTGGGTGGAGTTTGAAGACTCTTGGGAAAGCCTCAFYKTARKQNSCCATCCTGGGGCCACTGTTGGGGGTGGGAGTGAGCCCACCACAGAGGCCACAGGCAGGCCCCCACTTCAGGCCCAAGGCCTGGGGCGGGGIMGGAACAGTCACTGGGTCTCAGATTCTGAGACTGTTGTTTAGCTTACCTTTCTGCTAGGATTGGCTTCCCGCAGAGGGCAGGGCCCATCCTAAGCAGCTTCCAAGTCCCACAAAGGTGGCTTGTGGGAGGATTTGGAAGGAGCTGCATTGTGGGCGGGGAGTGTGTGGGTTGGGTTCGTACCAGCAAGTAGACTAGGAACTGAGCCCAGGAAAGGGGGATGTTTTCCTGGTGTTTGGATGGTCAGCTGGGAGTGTCCATCATCAGGGGAAGATCAAACACAGGTGCACTCAGCTGCCCAGGGCCTCTGGGACACTTGCCTTGACTTGCAACTTGCCTTGAACATCACGATCAAAGCAGCAGGTGCTGTGGTCTCTCAAAATTGATTTTTATTTGACTCTGTGGCTCTAAGACTGCCTTGAACCGCCTGAGGCCTATGCATCTGAACAAGTGGGTCTCTCCCTTGAGCACCAGGAGTGGGTGCCAGCCGGCCCCGAGGATTCCCAGCACCCCACCTATGGTCTTGCCAGCATAGGCTTGCTAGTTCCTTCTTGGTCAGAGGTAGCTGCAGAGGGGGGAGGCCAAGGGTTTGGTCTAAGCTGTGCCCTGCCACCTGGCAGGAGGCCCACTCACTGCCCAAGTCATGGCAACAGGCTGGAGCAGCCCAGGAGATGGGCCTAAAATGTTCTGGATCCCTTGGGTCCTAGTGTTATGTTCCAGTCTGCCCACCTGTGCTCAGGATGCAGCCCTGGGATCCAGCACCCATGGAAGCTTCTGCTGGGATGGTGTCACCTATGGGTTTTGAACCAGTGTGGTATGGTCCTTGGGAGCTCTGCTCTGAGCTTGCCACACTGCTGAGAGCACCCACTGTCCTGACCAGAGTCTCAGTGGTCCTGACCCCCAATGTGGGCAGGGGCTGGGCAGGAGGGTGGGGTCTGCTGTGGGTTCAGAGGACTCCACCTCCTGGCTGGTTTACCTGCTGCTGCCCATTTTCTCTGGGTACTGCTGGCCAGAGGACTTTAGCCTACCCCTGAAGAGCCTGTCCATGTCATTTTCCTACTGCCATAGATACCCTAAGCCCAGGGCCCCTTGAGGCCCAGACTCAGCCTGCCCACTGGTGCCGGAGACGGAGTGGAGTGGGCCTGGATCCGAGGGATGCTACCTCTCCCTTTCCCACTTGAGGACCCTGGGGAGAGATGGGGGCGGGGAAAATGGAGGTATGAATTTGGGGTAAGAGGAAGTGAGATCTCCGCTTGCAGGTCAGCCCCTGCCTTGCAGGGCGGGCTGGCTTGACTCAGGCCCTGTGAGATAGAGGGCCCAGCCCAGCCCCACCCACAGATCCCCTGCTCCTGTTGTGTTCTGTTGTAAATCATTTGGCGAGACTGTATTTTAGTAACTGCTGCCTAACTTCCCTGTGTTCTATTTGAGAGGCGCCTGTCTGGATAAAGTTGTCTTGAAATTTCAAAAAAAAAAAAAAAAAASEQ ID NO.: 26 SEQ ID NO.: 73CGCTGTCGCCGCCAGTAGCAGCCTTCGCCAGCAGCGCCGCGGCGGAACCGGGCGCAGGGGAGCGAGCCCGGCCCCGCCAGCCCAGCCMDHYDSQQTNDYMQCAGCCCAGCCCTACTCCCTCCCCACGCCAGGGCAGCAGCCGTTGCTCAGAGAGAAGGTGGAGGAAGAAATCCAGACCCTAGCACGCGPEEDWDRDLLLDPACGCACCATCATGGACCATTATGATTCTCAGCAAACCAACGATTACATGCAGCCAGAAGAGGACTGGGACCGGGACCTGCTCCTGGACWEKQQRKTFTAWCNCCGGCCTGGGAGAAGCAGCAGAGAAAGACATTCACGGCATGGTGTAACTCCCACCTCCGGAAGGCGGGGACACAGATCGAGAACATCSHLRKAGTQIENIEGAAGAGGACTTCCGGGATGGCCTGAAGCTCATGCTGCTGCTGGAGGTCATCTCAGGTGAACGCTTGGCCAAGCCAGAGCGAGGCAAGEDFRDGLKLMLLLEATGAGAGTGCACAAGATCTCCAACGTCAACAAGGCCCTGGATTTCATAGCCAGCAAAGGCGTCAAACTGGTGTCCATCGGAGCCGAAVISGERLAKPERGKGAAATCGTGGATGGGAATGTGAAGATGACCCTGGGCATGATCTGGACCATCATCCTGCGCTTTGCCATCCAGGACATCTCCGTGGAAMRVHKISNVNKALDGAGACTTCAGCCAAGGAAGGGCTGCTCCTGTGGTGTCAGAGAAAGACAGCCCCTTACAAAAATGTCAACATCCAGAACTTCCACATAFIASKGVKLVSIGAAGCTGGAAGGATGGCCTCGGCTTCTGTGCTTTGATCCACCGACACCGGCCCGAGCTGATTGACTACGGGAAGCTGCGGAAGGATGATEEIVDGNVKMTLGMCCACTCACAAATCTGAATACGGCTTTTGACGTGGCAGAGAAGTACCTGGACATCCCCAAGATGCTGGATGCCGAAGACATCGTTGGAIWTIILRFAIQDISACTGCCCGACCGGATGAGAAAGCCATCATGACTTACGTGTCTAGCTTCTACCACGCCTTCTCTGGAGCCCAGAAGGCGGAGACAGCAVEETSAKEGLLLWCGCCAATCGCATCTGCAAGGTGTTGGCCGTCAACCAGGAGAACGAGCAGCTTATGGAAGACTACGAGAAGCTGGCCAGTGATCTGTTGQRKTAPYKNVNIQNGAGTGGATCCGCCGCACAATCCCGTGGCTGGAGAACCGGGTGCCCGAGAACACCATGCATGCCATGCAACAGAAGCTGGAGGACTTCFHISWKDGLGFCALCGGGACTACCGGCGCCTGCACAAGCCGCCCAAGGTGCAGGAGAAGTGCCAGCTGGAGATCAACTTCAACACGCTGCAGACCAAGCTGIHRHRPELIDYGKLCGGCTCAGCAACCGGCCTGCCTTCATGCCCTCTGAGGGCAGGATGGTCTCGGACATCAACAATGCCTGGGGCTGCCTGGAGCAGGTGRKDDPLTNLNTAFDGAGAAGGGCTATGAGGAGTGGTTGCTGAATGAGATCCGGAGGCTGGAGCGACTGGACCACCTGGCAGAGAAGTTCCGGCAGAAGGCCVAEKYLDIPKMLDATCCATCCACGAGGCCTGGACTGACGGCAAAGAGGCCATGCTGCGACAGAAGGACTATGAGACCGCCACCCTCTCGGAGATCAAGGCCEDIVGTARPDEKAICTGCTCAAGAAGCATGAGGCCTTCGAGAGTGACCTGGCTGCCCACCAGGACCGTGTGGAGCAGATTGCCGCCATCGCACAGGAGCTCMTYVSSFYHAFSGAAATGAGCTGGACTATTATGACTCACCCAGTGTCAACGCCCGTTGCCAAAAGATCTGTGACCAGTGGGACAATCTGGGGGCCCTAACTQKAETAANRICKVLCAGAAGCGAAGGGAAGCTCTGGAGCGGACCGAGAAACTGCTGGAGACCATTGACCAGCTGTACTTGGAGTATGCCAAGCGGGCTGCAAVNQENEQLMEDYECCCTTCAACAACTGGATGGAGGGGGCCATGGAGGACCTGCAGGACACCTTCATTGTGCACACCATTGAGGAGATCCAGGGACTGACCKLASDLLEWIRRTIACAGCCCATGAGCAGTTCAAGGCCACCCTCCCTGATGCCGACAAGGAGCGCCTGGCCATCCTGGGCATCCACAATGAGGTGTCCAAGPWLENRVPENTMHAATTGTCCAGACCTACCACGTCAATATGGCGGGCACCAACCCCTACACAACCATCACGCCTCAGGAGATCAATGGCAAATGGGACCACMQQKLEDFRDYRRLGTGCGGCAGCTGGTGCCTCGGAGGGACCAAGCTCTGACGGAGGAGCATGCCCGACAGCAGCACAATGAGAGGCTACGCAAGCAGTTTHKPPKVQEKCQLEIGGAGCCCAGGCCAATGTCATCGGGCCCTGGATCCAGACCAAGATGGAGGAGATCGGGAGGATCTCCATTGAGATGCATGGGACCCTGNFNTLQTKLRLSNRGAGGACCAGCTCAGCCACCTGCGGCAGTATGAGAAGAGCATCGTCAACTACAAGCCAAAGATTGATCAGCTGGAGGGCGACCACCAGPAFMPSEGRMVSDICTCATCCAGGAGGCGCTCATCTTCGACAACAAGCACACCAACTACACCATGGAGCACATCCGTGTGGGCTGGGAGCAGCTGCTCACCNNAWGCLEQVEKGYACCATCGCCAGGACCATCAATGAGGTAGAGAACCAGATCCTGACCCGGGATGCCAAGGGCATCAGCCAGGAGCAGATGAATGAGTTCEEWLLNEIRRLERLCGGGCCTCCTTCAACCACTTTGACCGGGATCACTCCGGCACACTGGGTCCCGAGGAGTTCAAAGCCTGCCTCATCAGCTTGGGTTATDHLAEKFRQKASIHGATATTGGCAACGACCCCCAGGGAGAAGCAGAATTTGCCCGCATCATGAGCATTGTGGACCCCAACCGCCTGGGGGTAGTGACATTCEAWTDGKEAMLRQKCAGGCCTTCATTGACTTCATGTCCCGCGAGACAGCCGACACAGATACAGCAGACCAAGTCATGGCTTCCTTCAAGATCCTGGCTGGGDYETATLSEIKALLGACAAGAACTACATTACCATGGACGAGCTGCGCCGCGAGCTGCCACCCGACCAGGCTGAGTACTGCATCGCGCGGATGGCCCCCTACKKHEAFESDLAAHQACCGGCCCCGACTCCGTGCCAGGTGCTCTGGACTACATGTCCTTCTCCACGGCGCTGTACGGCGAGAGTGACCTCTAATCCACCCCGDRVEQIAAIAQELNCCCGGCCGCCCTCGTCTTGTGCGCCGTGCCCTGCCTTGCACCTCCGCCGTCGCCCATCTCCTGCCTGGGTTCGGTTTCAGCTCCCAGELDYYDSPSVNARCCCTCCACCCGGGTGAGCTGGGGCCCACGTGGCATCGATCCTCCCTGCCCGCGAAGTGACAGTTTACAAAATTATTTTCTGCAAAAAAQKICDQWDNLGALTGAAAAAAAAGTTACGTTAAAAACCAAAAAACTACATATTTTATTATAGAAAAAGTATTTTTTCTCCACCAGACAAATGGAAAAAAAGQKRREALERTEKLLAGGAAAGATTAACTATTTGCACCGAAATGTCTTGTTTTGTTGCGACATAGGAAAATAACCAAGCACAAAGTTATATTCCATCCTTTTETIDQLYLEYAKRATACTGATTTTTTTTTCTTCTATCTGTTCCATCTGCTGTATTCATTTCTCCAATCTCATGTCCATTTTGGTGTGGGAGTCGGGGTAGGAPFNNWMEGAMEDLGGGTACTCTTGTCAAAAGGCACATTGGTGCGTGTGTGTTTGCTAGCTCACTTGTCCATGAAAATATTTTATGATATTAAAGAAAATCQDTFIVHTIEEIQG TTTTG LTTAHEQFKATLPD ADKERLAILGIHNE VSKIVQTYHVNMAGTNPYTTITPQEING KWDHVRQLVPRRDQ ALTEEHARQQHNER LRKQFGAQANVIGPWIQTKMEEIGRISI EMHGTLEDQLSHLR QYEKSIVNYKPKID QLEGDHQLIQEALIFDNKHTNYTMEHIR VGWEQLLTTIARTI NEVENQILTRDAKG ISQEQMNEFRASFNHFDRDHSGTLGPEE FKACLISLGYDIGN DPQGEAEFARIMSI VDPNRLGVVTFQAFIDFMSRETADTDTA DQVMASFKILAGDK NYITMDELRRELPP DQAEYCIARMAPYTGPDSVPGALDYMSF STALYGESDL SEQ ID NO.: 27 SEQ ID NO.: 74TGCGGGCAGGATTCACGCCGCTGTGACCCGGAGGTCCTCAGGGGGCGAAGCCCCGGCCTAGGCCTCGCGGAGATGCCCAGCTGCGGTMPSCGACTCGAAAVGCTTGTACTTGCGGCGCGGCGGCCGTCCGGCTCATCACCTCCTCACTCGCCTCCGCGCAGAGAGGTATTTCTGGTGGTCGCATTCATRLITSSLASAQRGIATGTCAGTTTTAGGAAGGCTTGGGACATTTGAAACTCAGATTCTGCAAAGAGCTCCTCTTAGATCCTTTACAGAAACACCAGCATACSGGRIHMSVLGRLGTTTGCCTCAAAAGATGGGATAAGTAAAGATGGTTCTGGAGATGGAAATAAGAAATCAGCAAGTGAGGGAAGTAGTAAGAAATCAGGCTFETQILQRAPLRSTCTGGGAATTCTGGGAAAGGTGGAAACCAGCTGCGCTGTCCTAAATGTGGCGACTTGTGCACACATGTAGAGACCTTTGTATCATCCFTETPAYFASKDGIACCCGTTTTGTCAAGTGTGAAAAGTGTCATCATTTTTTTGTTGTGCTATCTGAAGCAGACTCAAAGAAAAGCATAATTAAAGAACCTSKDGSGDGNKKSASGAATCAGCAGCAGAAGCTGTAAAATTGGCATTCCAACAGAAACCACCACCTCCCCCTAAGAAGATTTATAACTACCTCGACAAGTATEGSSKKSGSGNSGKGTTGTTGGCCAGTCATTTGCTAAGAAGGTGCTTTCAGTTGCTGTGTACAATCATTATAAGAGAATATATAATAATATCCCAGCTAATGGNQLRCPKCGDLCCTGAGACAGCAAGCAGAGGTTGAGAAGCAGACATCATTAACACCAAGAGAGTTAGAAATAAGAAGACGGGAGGATGAGTACAGATTTTHVETFVSSTRFVKACAAAATTGCTTCAGATTGCTGGAATTAGCCCACATGGTAATGCTTTAGGAGCATCAATGCAGCAACAGGTAAATCAACAAATACCTCEKCHHFFVVLSEACAGGAAAAACGAGGAGGTGAAGTATTGGATTCTTCTCATGATGACATAAAACTTGAAAAAAGTAATATTTTGCTGCTTGGACCAACTDSKKSIIKEPESAAGGGTCAGGTAAAACTCTGCTGGCACAAACCCTAGCTAAATGCCTTGATGTCCCTTTTGCTATCTGTGACTGTACAACTTTGACTCAGEAVKLAFQQKPPPPGCTGGATATGTAGGCGAAGATATTGAATCTGTGATTGCAAAACTACTCCAAGATGCCAATTATAATGTGGAAAAAGCACAACAAGGAPKKIYNYLDKYVVGATTGTCTTTCTGGATGAAGTAGATAAGATTGGCAGTGTGCCAGGCATTCATCAATTACGGGATGTAGGTGGAGAAGGCGTTCAGCAAQSFAKKVLSVAVYNGGCTTATTAAAACTACTAGAAGGCACAATAGTCAATGTTCCAGAAAAGAATTCCCGAAAGCTCCGTGGAGAAACAGTTCAAGTTGATHYKRIYNNIPANLRACAACAAACATCCTGTTTGTGGCATCTGGTGCTTTCAATGGTTTAGACAGAATCATCAGCAGGAGGAAAAATGAAAAGTATCTTGGAQQAEVEKQTSLTPRTTTGGAACACCATCTAATCTGGGAAAAGGCAGAAGGGCTGCAGCTGCTGCAGACCTTGCTAATCGAAGTGGGGAATCGAATACTCACELEIRRREDEYRFTCAAGACATTGAAGAAAAAGATCGGTTATTGCGTCATGTGGAAGCCAGAGATCTGATTGAGTTTGGCATGATTCCTGAGTTTGTGGGAKLLQIAGISPHGNACGGTTGCCTGTGGTGGTTCCATTGCATAGCCTAGATGAGAAAACACTTGTACAAATATTAACTGAGCCACGAAATGCTGTTATTCCTLGASMQQQVNQQIPCAGTACCAGGCCTTATTCAGCATGGATAAGTGTGAACTGAATGTTACTGAGGATGCTTTGAAAGCTATAGCCAGATTGGCACTAGAAQEKRGGEVLDSSHDCGAAAAACAGGTGCACGAGGCCTTCGGTCCATAATGGAAAAGCTGTTACTAGAACCAATGTTTGAAGTCCCTAATTCTGATATCGTADIKLEKSNILLLGPTGTGTGGAGGTTGACAAAGAAGTAGTAGAAGGAAAAAAGGAACCAGGATACATCCGGGCTCCAACAAAAGAATCCTCTGAAGAGGAGTGSGKTLLAQTLAKTATGACTCTGGAGTTGAAGAAGAAGGATGGCCCCGCCAAGCAGATGCTGCAAACAGCTAAACTGTCATATTGCTGTCTTGTATATACCLDVPFAICDCTTLAGCTTTTCCTTCTTTTGTTTAGGATCATAATTGTCTCTACAGTCTGATATTAAAGGCATTGGATCTATCTTGGATATCATACATGGTTQAGYVGEDIESVICAGAGAAGCCTTTAGGAGAAGAATCAGATCATGTATATAATTGTAACATCACATTGATTTTACGGAAGATGTTATATGGACTTTAATAKLLQDANYNVEKAGACACAATGTTTAGAGATAAAATGTACATTATTTTGGTTCAGTTTTTTAAAAAAAATATGCTTTAACAAAATTCTTAGGAATTCTTTQQGIVFLDEVDKIGTAAGCAATGCAGGTATTGCGATAACTGTAGATTTTACAATAATGTTACTCTACAAATGGGAAAATAAATTCTTTAAAATTGAATATTSVPGIHQLRDVGGE GA GVQQGLLKLLEGTI VNVPEKNSRKLRGE TVQVDTTNILFVASGAFNGLDRIISRRK NEKYLGFGTPSNLG KGRRAAAAADLANR SGESNTHQDIEEKDRLLRHVEARDLIEF GMIPEFVGRLPVVV PLHSLDEKTLVQIL TEPRNAVIPQYQALFSMDKCELNVTEDA LKAIARLALERKTG ARGLRSIMEKLLLE PMFEVPNSDIVCVEVDKEVVEGKKEPGY IRAPTKESSEEEYD SGVEEEGWPRQADA ANS SEQ ID NO.: 28 SEQ IDNO.: 75GGCGCCCAAGCCGCCGCCGCCAGATCGGTGCCGATTCCTGCCCTGCCCCGACCGCCAGCGCGACCATGTCCCATCACTGGGGGTACGMSHHWGYGKHNGPEGCAAACACAACGGACCTGAGCACTGGCATAAGGACTTCCCCATTGCCAAGGGAGAGCGCCAGTCCCCTGTTGACATCGACACTCATAHWHKDFPIAKGERQCAGCCAAGTATGACCCTTCCCTGAAGCCCCTGTCTGTTTCCTATGATCAAGCAACTTCCCTGAGGATCCTCAACAATGGTCATGCTTSPVDIDTHTAKYDPTCAACGTGGAGTTTGATGACTCTCAGGACAAAGCAGTGCTCAAGGGAGGACCCCTGGATGGCACTTACAGATTGATTCAGTTTCACTSLKPLSVSYDQATSTTCACTGGGGTTCACTTGATGGACAAGGTTCAGAGCATACTGTGGATAAAAAGAAATATGCTGCAGAACTTCACTTGGTTCACTGGALRILNNGHAFNVEFACACCAAATATGGGGATTTTGGGAAAGCTGTGCAGCAACCTGATGGACTGGCCGTTCTAGGTATTTTTTTGAAGGTTGGCAGCGCTADDSQDKAVLKGGPLAACCGGGCCTTCAGAAAGTTGTTGATGTGCTGGATTCCATTAAAACAAAGGGCAAGAGTGCTGACTTCACTAACTTCGATCCTCGTGDGTYRLIQFHFHWGGCCTCCTTCCTGAATCCCTGGATTACTGGACCTACCCAGGCTCACTGACCACCCCTCCTCTTCTGGAATGTGTGACCTGGATTGTGCSLDGQGSEHTVDKKTCAAGGAACCCATCAGCGTCAGCAGCGAGCAGGTGTTGAAATTCCGTAAACTTAACTTCAATGGGGAGGGTGAACCCGAAGAACTGAKYAAELHLVHWNTKTGGTGGACAACTGGCGCCCAGCTCAGCCACTGAAGAACAGGCAAATCAAAGCTTCCTTCAAATAAGATGGTCCCATAGTCTGTATCCYGDFGKAVQQPDGLAAATAATGAATCTTCGGGTGTTTCCCTTTAGCTAAGCACAGATCTACCTTGGTGATTTGGACCCTGGTTGCTTTGTGTCTAGTTTTCAVLGIFLKVGSAKPTAGACCCTTCATCTCTTACTTGATAGACTTACTAATAAAATGTGAAGACTAGACCAATTGTCATGCTTGACACAACTGCTGTGGCTGGLQKVVDVLDSIKTGTTGGTGCTTTGTTTATGGTAGTAGTTTTTCTGTAACACAGAATATAGGATAAGAAATAAGAATAAAGTACCTTGACTTTGTTCACAKGKSADFTNFDPRGGCATGTAGGGTGATGAGCACTCACAATTGTTGACTAAAATGCTGCTTTTAAAACATAGGAAAGTAGAATGGTTGAGTGCAAATCCATLLPESLDYWTYPGSAGCACAAGATAAATTGAGCTAGTTAAGGCAAATCAGGTAAAATAGTCATGATTCTATGTAATGTAAACCAGAAAAAATAAATGTTCALTTPPLLECVTWIVTGATTTCAAGATGTTATATTAAAGAAAAACTTTAAAAATTATTATATATTTATAGCAAAGTTATCTTAAATATGAATTCTGTTGTAALKEPISVSSEQVLKTTTAATGACTTTTGAATTACAGAGATATAAATGAAGTATTATCTGTAAAAATTGTTATAATTAGAGTTGTGATACAGAGTATATTTCFRKLNFNGEGEPEECATTCAGACAATATATCATAACTTAATAAATATTGTATTTTAGATATATTCTCTAATAAAATTCAGAATTCTLMVDNWRPAQPLKN RQIKASFK SEQ ID NO.: 29 SEQ ID NO.: 76GCTGAGCGCGGGCGCGGGGCCGCTACGTGCGCGGGGAGCGCGGGGAGCGCGGGGAGCGCGGGGCTGCGCTCGTGTGCGCTCCTGGGCMFPEQQKEEFVSVWGCTCGCCGCCGCCGCTGCCGCCGCGCGCCTTTGAGTCAGCAAACTCCGCGGCCCGCAAGCCCGGCTCGGCCCGGCCCTGCTCTGTTCVRDPRIQKEDFWHSTGCCCGGAGGAGCCGCCCATTGATCGTGTCCTGTGCTGAAGATGTTTCCGGAACAACAGAAAGAGGAATTTGTAAGTGTCTGGGTTCYIDYEICIHTNSMCGAGATCCTAGGATTCAGAAGGAGGACTTCTGGCATTCTTACATTGACTATGAGATATGTATTCATACTAATAGCATGTGTTTTACAAFTMKTSCVRRRYRETGAAAACATCCTGTGTACGAAGAAGATATAGAGAATTCGTGTGGCTGAGGCAGAGACTCCAAAGTAATGCGTTGCTGGTACAACTGCFVWLRQRLQSNALLCAGAACTTCCATCTAAAAACCTGTTTTTCAACATGAACAATCGCCAGCACGTGGATCAGCGTCGCCAGGGTCTGGAAGATTTCCTCAVQLPELPSKNLFFNGAAAAGTCCTACAGAATGCACTTTTGCTTTCAGATAGCAGCCTTCACCTCTTCTTACAGAGCCATCTGAATTCAGAAGACATTGAGGMNNRQHVDQRRQGLCGTGTGTTTCTGGGCAGACTAAGTACTCTGTGGAAGAAGCAATTCACAAGTTTGCCTTAATGAATAGACGTTTCCCTGAAGAAGATGEDFLRKVLQNALLLAAGAAGGAAAAAAAGAAAATGATATAGATTATGATTCAGAAAGTTCATCCTCTGGGCTTGGACACAGTAGTGATGACAGCAGTTCACSDSSLHLFLQSHLNATGGATGTAAAGTAAATACAGCTCCGCAGGAATCCTGAAAAATAATTCTAATGTTACTATCTTAGGAATAGCAAATTATGTCCAGTCSEDIEACVSGQTKYATAGAGAAGAAAGCTTCATAATAATACATTCTTACCTAAAGCTCACTGTCATGATGTTAGGTATTTAAATTCTTAAAGATGTTGGGTSVEEAIHKFALMNRTGTTTATTAGTGGTATTTTTATGTTGTCTTATTTTAGGTAAGCTTCTGTGTAAAGCTAAAAATCCTGTGAATACAATACTATCCTTTRFPEEDEEGKKENDACAGGCAGACATTATTGGTAAACAAGATCTTGCCCTCCAATGAAATGACTTACATGTTTTAAAAAACCGAGTTGGTTTTATTGAATTIDYDSESSSSGLGHTAAAAAGATAGGTAACTAAGTAGCATTTAAAATCAAGATAGAGCATTCCTTCTTGTATCAGTGGGGCAGTGTTACCATAAACACGGTSSDDSSSHGCKVNTGTATATGTTGTTAAACCCTATGAAGAGTAACAGTGTAGACCAGACTGCCTCTCTCAGATATGTGCCTGATATTTTGTGGATACCTCCAPQESCCTGCACTGGCAAAACACTATGCTTTTGGGTGTTAGACTGAAATATTTTAAGAGTATTTAACCTTTCCAGTATTCTGTTTCACGCTTAGATGGAAATGTATCTTATGAATAGAGACATATTAAAATAATGTTTACATCTTAGAAAAAACATAGATAGTGCTAGTAATATTACTTATAACTGTAATATATAGATTCAGAAATACATTTTCATTATCCAAAATCAGCTTCAACAAATGGTTTCTGGAGACAAATAATTTGTTTTCATTATCATTGTATAATCAGGTTAATGATTTATTTTTTGACTAAATGTGCAATTTCTTATCACTAGATAACTTTCAGTATCAGTGGTGGTTACTTATTACTTAAATCAGAGGAAGGATTTTATAAAGATTAATAAATTTAATTTTACCAATAAATATTCCCATAATTTAGAAAAGGATGTCGACTTGCTAATTTCAGAAATAATTATTCATTTTTAAAAAGCCCCTTTTAAAGCATCTACTTGAAGATTGGTATAATTTTCATAAAATGTCTTTTTTTTTAGTGTCCCAAAGATATCTTAGATAAACTATTTTGAAGTTCAGATTTCAGATGAGGCAACATTTTCTTGAGATAATTACCCAAGTTTCATCCATGTTGAATGGTACAAAATATTTCTGTGAAACTAACAGGAAGATATTTTCAGATAACTAGGATAACTTGTTGCTTTGTTACCCAGCCTAATTGAAGAGTGGCAGAGGCTACTACAAAAAGCAACCTTTTCATTTTCACTAAGAGTTTAAAAGCTATTGTATTATTAAAAAGTCTTTACAATGCTTGTTTCAAAGAACCAACAGAAAAAAAAGCTAAGAAAACTGAGAACTAACATTAAAAAAATTAAATTTAGAATAAGAATGATTTCTTTAATTTGTCCTTTTTTTCTTTGGTCTAAAACATTATTAAATTTTTGTAAATATTTTGATTTAATGTGTCTTAGATCCTCATTATTTTAATACAGGAAAAGAAAAGATTTAGTAATTTCTTACCATGCTAATATGTAAAGTTCATGCCATCCAGGCATTTAAGAGCGATCCTCATCCCTTCAGCAATATGTATTTGAGTTCACACTATTTCTGTTTTACAGCAGTTTTGAAAAACACATACTATGCCACCAATTGTCATATTATTTTTAGATGATGTAACATAGCCATCAAAATTAATATTATGTAATGCCTAATACTTAGTATGTAAATGTCACGAGATCATTTTTACATTAAACGTGAAAAAAAATCAAAAAAAAAAAAAAA SEQID NO.: 30 SEQ ID NO.: 77GAACCTCCTCGCGACTTTCCAAGGTATCTTTCAGATGAAGGCATTGAAGCTTGCACAAGCTCTCCAGACAAAGTCAATGTAAATGACMLRLQMTDGHISCTATCATCCTGATTGCTCTCAATATCTGAGAACAATTGGCAAGAAATTCCTCCCCAGTGACATCAATAGTGGAAAGGTAGAAAAGCTCGAVEFSYMSKISLNTAAGGTCCATGTGTTTTGCAAATTCAAAAAATTCGCAATGTTGCTGCACCAAAGGATAATGAAGAATCTCAGGCTGCACCAAGGATGCPPGTKVKLSGIVDITGCGATTACAGATGACTGATGGTCATATAAGTTGCACAGCAGTAGAATTTAGTTATATGTCAAAAATAAGCCTGAACACACCACCTGKNGFLLLNDSNTTVGAACTAAAGTTAAGCTCTCAGGCATTGTTGACATAAAAAATGGATTCCTGCTCTTGAATGACTCTAACACCACAGTTCTTGGTGGTGLGGEVEHLIEKWELAAGTGGAACACCTTATTGAGAAATGGGAGTTACAGAGAAGCTTATCAAAACACAATAGAAGCAATATTGGAACTGAAGGTGGACCACQRSLSKHNRSNIGTCGCCTTTTGTGCCTTTTGGACAGAAGTGTGTATCTCATGTCCAAGTGGATAGCAGAGAACTTGATCGAAGAAAAACATTGCAAGTTAEGGPPPFVPFGQKCCAATGCCTGTCAAACCTACAAATGATAATGATGAATTTGAAAAGCAAAGGACGGCTGCTATTGCTGAAGTTGCAAAGAGCAAGGAAAVSHVQVDSRELDRRCCAAGACATTTGGAGGAGGTGGTGGTGGTGCTAGAAGTAATCTCAATATGAATGCTGCTGGTAACCGAAATAGGGAAGTTTTACAGAKTLQVTMPVKPTNDAAGAAAAGTCAACCAAATCAGAGGGAAAACATGAAGGTGTCTATAGAGAACTGGTTGATGAGAAAGCTCTGAAGCACATAACGGAAANDEFEKQRTAAIAETGGGCTTCAGTAAGGAAGCATCGAGGCAAGCTCTTATGGATAATGGCAACAACTTAGAAGCAGCACTGAACGTACTTCTTACAAGCAVAKSKETKTFGGGGATAAACAGAAACCTGTTATGGGTCCTCCTCTGAGAGGTAGAGGAAAAGGCAGGGGGCGAATAAGATCTGAAGATGAAGAGGACCTGGGGARSNLNMNAAGNGAAATGCAAGGCCATCAGCACCAAGCACATTATTTGATTTCTTGGAATCTAAAATGGGAACTTTGAATGTGGAAGAACCTAAATCACRNREVLQKEKSTKSAGCCACAGCAGCTTCATCAGGGACAATACAGATCATCAAATACTGAGCAAAATGGAGTAAAAGATAATAATCATCTGAGACATCCTCEGKHEGVYRELVDECTCGAAATGATACCAGGCAGCCAAGAAATGAAAAACCGCCTCGTTTTCAAAGAGACTCCCAAAATTCAAAGTCAGTTTTAGAAGGCAKALKHITEMGFSKEGTGGATTACCTAGAAATAGAGGTTCTGAAAGACCAAGTACTTCTTCAGTATCTGAAGTATGGGCTGAAGACAGAATCAAATGTGATAASRQALMDNGNNLEGACCGTATTCTAGATATGACAGAACTAAAGATACTTCATATCCTTTAGGTTCTCAGCATAGTGATGGTGCTTTTAAAAAAAGAGATAAALNVLLTSNKQKPACTCTATGCAAAGCAGATCAGGAAAAGGTCCCTCCTTTGCAGAGGCAAAAGAAAATCCACTTCCTCAAGGATCTGTAGATTATAATAVMGPPLRGRGKGRGATCAAAAACGTGGAAAAAGAGAAAGCCAAACATCTATTCCTGACTATTTTTATGACAGGAAATCACAAACAATAAATAATGAAGCTTRIRSEDEEDLGNARTCAGTGGTATAAAAATTGAAAAACATTTTAATGTAAATACTGATTATCAGAATCCAGTTCGAAGTAATAGTTTCATTGGTGTTCCAAPSAPSTLFDFLESKATGGAGAAGTAGAAATGCCACTGAAAGGAAGACGAATAGGACCTATTAAGCCAGCAGGACCTGTCACAGCTGTACCCTGTGATGATAMGTLNVEEPKSQPQAAATATTTTACAATAGTGGGCCCAAACGAAGATCTGGGCCAATTAAGCCAGAAAAAATACTAGAATCATCTATTCCTATGGAGTATGQLHQGQYRSSNTEQCAAAAATGTGGAAACCTGGAGATGAATGTTTTGCACTTTATTGGGAAGACAACAAGTTTTACCGGGCAGAAGTTGAAGCCCTCCATTNGVKDNNHLRHPPRCTTCGGGTATGACAGCAGTTGTTAAATTCATTGACTACGGAAACTATGAAGAGGTGCTACTGAGCAATATCAAGCCCATTCAAACAGNDTRQPRNEKPPRFAGGCATGGGAGGAAGAAGGCACCTACGATCAAACTCTGGAGTTCCGTAGGGGAGGTGATGGCCAGCCAAGACGATCCACTCGGCCAAQRDSQNSKSVLEGSCCCAACAGTTTTACCAACCACCCCGGGCTCGGAACTAATAGGAAAAGACTCTTTGTGAAGAAACGAGCCAGTGACTGAAACACCCTGGLPRNRGSERPSTSGTGGAAACCTGTTGACAGACCTTCCACTTTCTCTTCAGAATAAGTAGCTGTGGTGGATATTATTATTTGAAGAAAGAAAAAACAGATSVSEVWAEDRIKCDTTTAGGGTGGAAAAAACAGTCAACTCACACAAAGAATGGAAAAAAATACTGAGTTAAATTAAGCAAATACCTTTTACAAGTGAAAGGRPYSRYDRTKDTSYAAGAATTTTTCTTCTGCCGTCAATAAAACCATTGTGCTATTATTGTTTAAAAAAAAAAAAAAAAAPLGSQHSDGAFKKR DNSMQSRSGKGPSF AEAKENPLPQGSVD YNNQKRGKRESQTSIPDYFYDRKSQTIN NEAFSGIKIEKHFN VNTDYQNPVRSNSF IGVPNGEVEMPLKGRRIGPIKPAGPVTA VPCDDKIFYNSGPK RRSGPIKPEKILES SIPMEYAKMWKPGDECFALYWEDNKFYR AEVEALHSSGMTAV VKFIDYGNYEEVLL SNIKPIQTEAWEEEGTYDQTLEFRRGGD GQPRRSTRPTQQFY QPPRARN SEQ ID NO.: 31 SEQ ID NO.: 78ATAAATATCAGAGTGTGCTGCTGTGGCTTTGTGGAGCTGCCAGAGTAAAGCAAAGAGAAAGGAAGCAGGCCCGTTGGAAGTGGTTGTMWRSLGLALALCLLGACAACCCCAGCAATGTGGAGAAGCCTGGGGCTTGCCCTGGCTCTCTGTCTCCTCCCATCGGGAGGAACAGAGAGCCAGGACCAAAGPSGGTESQDQSSLCCTCCTTATGTAAGCAACCCCCAGCCTGGAGCATAAGAGATCAAGATCCAATGCTAAACTCCAATGGTTCAGTGACTGTGGTTGCTCTKQPPAWSIRDQDPMTCTTCAAGCCAGCTGATACCTGTGCATACTGCAGGCATCTAAATTAGAAGACCTGCGAGTAAAACTGAAGAAAGAAGGATATTCTAALNSNGSVTVVALLQTATTTCTTATATTGTTGTTAATCATCAAGGAATCTCTTCTCGATTAAAATACACACATCTTAAGAATAAGGTTTCAGAGCATATTCCASUYLCILQASKLETGTTTATCAACAAGAAGAAAACCAAACAGATGTCTGGACTCTTTTAAATGGAAGCAAAGATGACTTCCTCATATATGATAGATGTGGDLRVKLKKEGYSNICCGTCTTGTATATCATCTTGGTTTGCCTTTTTCCTTCCTAACTTTCCCATATGTAGAAGAAGCCATTAAGATTGCTTACTGTGAAAASYIVVNHQGISSRLGAAATGTGGAAACTGCTCTCTCACGACTCTCAAAGATGAAGACTTTTGTAAACGTGTATCTTTGGCTACTGTGGATAAAACAGTTGAKYTHLKNKVSEHIPAACTCCATCGCCTCATTACCATCATGAGCATCATCACAATCATGGACATCAGCACCTTGGCAGCAGTGAGCTTTCAGAGAATCAGCAVYQQEENQTDVWTLACCAGGAGCACCAAATGCTCCTACTCATCCTGCTCCTCCAGGCCTTCATCACCACCATAAGCACAAGGGTCAGCATAGGCAGGGTCALNGSKDDFLIYDRCCCCAGAGAACCGAGATATGCCAGCAAGTGAAGATTTACAAGATTTACAAAAGAAGCTCTGTCGAAAGAGATGTATAAATCAATTACTGRLVYHLGLPFSFLCTGTAAATTGCCCACAGATTCAGAGTTGGCTCCTAGGAGCTGATGCTGCCATTGTCGACATCTGATATTTGAAAAAACAGGGTCTGCTFPYVEEAIKIAYCAATCACCTGACAGTGTAAAGAAAACCTCCCATCTTTATGTAGCTGACAGGGACTTCGGGCAGAGGAGAACATAACTGAATCTTGTCAEKKCGNCSLTTLKDGTGACGTTTGCCTCCAGCTGCCTGACAAATAAGTCAGCAGCTTATACCCACAGAAGCCAGTGCCAGTTGACGCTGAAAGAATCAGGCEDFCKRVSLATVDKAAAAAAGTGAGAATGACCTTCAAACTAAATATTTAAAATAGGACATACTCCCCAATTTAGTCTAGACACAATTTCATTTCCAGCATTTVETPSPHYHHEHHTTTATAAACTACCAAATTAGTGAACCAAAAATAGAAATTAGATTTGTGCAAACATGGAGAAATCTACTGAATTGGCTTCCAGATTTTHNHGHQHLGSSELSAAATTTTATGTCATAGAAATATTGACTCAAACCATATTTTTTATGATGGAGCAACTGAAAGGTGATTGCAGCTTTTGGTTAATATGTENQQPGAPNAPTHPCTTTTTTTTTCTTTTTCCAGTGTTCTATTTGCTTTAATGAGAATAGAAACGTAAACTATGACCTAGGGGTTTCTGTTGGATAATTAGAPPGLHHHHKHKGQCAGTTTAGAATGGAGGAAGAACAACAAAGACATGCTTTCCATTTTTTTCTTTACTTATCTCTCAAAACAATATTACTTTGTCTTTTCHRQGHPENRDMPASAATCTTCTACTTTTAACTAATAAAATAAGTGGATTTTGTATTTTAAGATCCAGAAATACTTAACACGTGAATATTTTGCTAAAAAAGEDLQDLQKKLCRKRCATATATAACTATTTTAAATATCCATTTATCTTTTGTATATCTAAGACTCATCCTGATTTTTACTATCACACATGAATAAAGCCTTTCINQLLCKLPTDSEGTATCTTTCTTTCTCTAATGTTGTATCATACTCTTCTAAAACTTGAGTGGCTGTCTTAAAAGATATAAGGGGAAAGATAATATTGTCLAPRSUCCHCRHLITGTCTCTATATTGCTTAGTAAGTATTTCCATAGTCAATGATGGTTTAATAGGTAAACCAAACCCTATAAACCTGACCTCCTTTATGGFEKTGSAITUQCKETTAATACTATTAAGCAAGAATGCAGTACAGAATTGGATACAGTACGGATTTGTCCAAATAAATTCAATAAAAACCTTAAAGCTGAAANLPSLCSUQGLRAEAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAENITESCQURLPPA AUQISQQLIPTEAS ASURUKNQAKKUEU PSN SEQ ID NO.: 32 SEQ IDNO.: 79CCGGGGCCCTACACGCCAGACCTGGCTCGGGGTGGGAGTGCAGAGGCAACCAAAAAGGAACCCACACCTCCCTCCAGGGCCCGGGGCMHYVHVHRVTTQPRGCTGTCAGACGGGGCAGCAACCAGGAGATTCCCTGGGCCTGCAGGAAGCCCTTCCGCGGACCGAAAGATTGTTCCCCATTTTGGAGANKPQTKCPSGGQSQTGAAGAAACTGAGACTCAAAGCAGCTGAGTGACCTTCCCAAGGACACACACTGAACTGGGCGGTGATCAGGATCTGAATGCACAGGGGPRGQFLDTVLAAMCGGGTGTTCAGCGATTGTTTACTACGTTGAACGTGACCTCCAGGAAAGCAGTTCTGGCCGAGATCCCCTGACAACGCAAAGCAAGAACPIAMLLTADPGMPGTAACGTGGAAGGAGGCTCCCCAAGCTGGCTGGCCATTTTGCTGCTGTGTGTGGAGGTGCTGCCAGTGGCATGCCCAAACCCAAAGCPTCLWHTPHAKHKETGGAAGAGGAATAAATTACAAGTGGTCAAGGTTGCATCCTTTTGAGCCCAGGACCTGCTTGTAAGCCGAGAGGGTTCTCTGGCCCTAHLSIHLNMVPKCVHATCTAGCCAAGCACCATGGAGAGAATCAGTGCCTTCTTCAGCTCTATCTGGGACACCATCTTGACCAAACACCAAGAAGGCATCTACMHVTHTHTNSGSRYAACACCATCTGCCTGGGAGTCCTCCTGGGCCTGCCACTCTTGGTGATCATCACACTCCTCTTCATCTGTTGCCATTGCTGCTGGAGCVGKYILLIKWSLAMCCACCAGGCAAGAGGGGCCAGCAGCCAGAGAAGAACAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGGATGAAGAAGACCTCTGGATCYFVQGSTLSTVTKMTCTGCTCAACCCAAGCTTCTCCAGATGGAGAAGAGACCATCACTGCCTGTTTAGTTAGGCAGGAAGCAGAGGTGTTTCCTTTCTGGGSHGKALPDSDTYIQGCTAAGCCTCCTTCTGACCACACACAGACATTTCAGGAACCCCTGAAATAATGCACTATGTCCATGTCCACAGAGTAACTACTCAACFPNQQGPHTPSIPCAAGGAACAAACCTCAGACTAAGTGTCCCAGTGGAGGGCAGTCCCAGGGACCACGTGGACAATTCTTGGATACTGTCTTGGCAGCTATGTGTCCAATAGCAATGCTCCTTACTGCAGACCCAGGCATGCCTCCCACCTGTCTCTGGCATACCCCACATGCAAAGCACAAAGAACATTTATCCATACATCTCAATATGGTTCCCAAGTGTGTGCACATGCACGTAACACACACACACACAAATTCAGGTAGCAGGTACGTGGGCAAGTATATTCTGCTCATCAAATGGTCATTGGCTATGTACTTTGTGCAGGGAAGTACATTATCTACAGTCACAAAAATGTCTCATGGGAAAGCCTTGCCAGATTCAGACACATATATACAATTTCCTAACCAGCAAGGCCCCCATACACCATCTATTCCATAAACCACTCAGGTTACAGATGCATGCTTTCCTATTTCTAACTCTACACATAAACTTTTACTGGAAGTACTCATAATTGGACATTCCAGCAACCTGCTACAGTCCCCACCCTTGTGTGTCTTGATACAGACACACCAAGTTTCTGTGCCTCTGACCCCTCACCTGTGCCAAGATGTTTAAAGTGTGATGGTTCAAAATTCATTGAAAGCTCTTTTCTTGTAACTCATGACAAAGTCCGTCCTCATTGCCACTGAGAGGTGTTTAATGTGATCCAAGACCTCTCTGTGAAACATTACCCCCGCAAACCACTCAGCAAAGTGCCTTTCTCCAAGCAAGAACAAAGAGCTCTTGGTGGTGACTGCTAGAAAATTATGGAAGCCCACTCATTTATGTCAGTGGACTGCAACTGTGTACCTGTGCAATGTTTACAGATGGAAAGGGTGAGGAGATGCTACACCTGAGCTAGGTATCTCCTATATAACCAAAGTTTCCAGCAGGGAAGGAACTAGACAATCATCAGTGCAGTCTCACAGAAGGCAACACTGGAAGTGATGTCATAAGGTTGTGATGTGTGCACGGTATGGCACAGGTGGGATGCAGAGGTAACAGAGTTTAAATGAAAGTAGGATGAAGCTATAAAGAGGTTTATTTATATTTATATTGAAGCTCAGGCAAGTGCCTTGCACACAGTAGGTACTTATAACTAACTGTGGTTACTGTTGGATATGTGATGTTGTTAAGGGTAAGCTTGTAATACCTCACCAGTTCTCCCCGAGTGATCTTCTCTTCTAAGTGAGCCCACTAATTGCTGCAATGGATGAAATTGGGTGTTTAATGCTGGAGAGCACATGTAGGTGACACATGTGCCTTGAGGTATGTGAGGACATGTAAATTAGATCCACAGTGAGCTGAGGAGGGCTTTCCCCGCCAGAGTGAGGTTGGGAAGCAGAGTTAATCCACTTATAGGATGAACTGCTTGGTATTTTTATTGTATTGTGACTGTATTACAAAGATGGACAATTCACTCCTTGGGAGCAAGTTATGCTCTAGAAGTTTATTTACAAATATGCTGGGCAGCTCTCTTGAAATATTTTCCCAAGGAAGCTATTCTACACAGTGGCAAAATTGCTATCTAATTAATAATGTAGCTAAACTATGATATTTATAGTAGCAAAAAACTAAATTCTATAAGATTGCATTAAAGGAAAGATATATTCTATTTGCTCACTTGGGCTGCTTGGTACTCACCTGCCCTCCAGGTGTACTTTAGGCCTGTGGAGGGTGGGCATTTAGTGGTGACCCTTGCACCAGGGTTTTCTAACAGATGACCCTGTGAATCATAATTTAAACCTGCATATATTTTATAGCCAGTCACATTTGCCCTCTCACCCTATATGGCCATAAACTGCCTAAGCACTCAGGCCTCCCACTCATCAACCCCTTTGACCAGAGAAAGAAGCACTCTGGTTCTCTATCCCCTTGTCACATAGAGAGTTTGTCATGGGGCCTCTGGCTGTGCCCTTCACATAACAGAATGACTTGCCATCTGCCTGCACCAAACCCAGGGATGTGGAAGACATCTCCCCACAACTGCCACTGCTCACCAGGACAAGCTGCCCTTCCTGTCTCCACCTCTCAGTCCCCCTAGAATGGATGGCTGGGGAGAGGTGGAGGCTGACAGCTGAGACGTAGTGTCAGATATGATCTAGGAGGGCGGATCACCGGGATCCGGGACCATACAAGTAACATGGTTTCCATGGCAACTGCTTGCTCCTTTGAATTAAGACAGCAGTCAGTTGTCATTGCCATGACAAGGCCTCTATCTCCAGGCACAATGTCCCTGCTGTCTCCTAATCCAATGGACTTGCTCTCACCCCAGGGATGAAACACCCAGAAACTCACTTCTCAGTCACTTCCACAGCCGATGACTCAGAAGAGCCAAACCCAGAATGGGGCCTCTCTTTTCCCCATCACAGACTCCCCTGACAACCTTTCCTGGCGTAACTAGAGGAGTCCCAGTGCAGGATAGGCCCTAAACGTTTTGTTAAATAAACAGGTGCATGAAAGGAGCCTAAGGCCATTGTTGATATCCACTCTCTTCTTTCCACTTCCTTCTCATCTTTTTCTCCATGTTTTATGCTTCTCTGATTCCCTCTTCTGCCTGCACCAGACCAGCCCCAGCCCTTTATTCCTCTCCATTTTCACTCCTTCCAGCCTCTGTCCCTGAACTGCCACTGGCAACCCATGGGACCTCAGGACCAGAGACTGCTTGACTCATCTGGGGAGGGTAAGTTCACGGGGGACAAAAAAATGATTCCTAAAGAAGAGGCTTCCTAGACCAGCACAGGCTCGAGAAAGACATCCCCTAGGCCTGGACTTCTGAGCAGCTTTAGCCAGGCTCCGGACGGCAGCCAGAGGAGGCCTTTCCCCATTGCTCCTTTCCCCATTGCTCAATGGATTCCATGTTTCTTTTTCTTGGGGGGAGCAGGGAGGGAGAAAGGTAGAAAAATGGCAGCCACCTTTCCAAGAAAAATATAAAGGGTCCAAGCTGTATAGTATTTGTCAGTATTTTTTTCTGTAAAATTCAAACACACACAAAAGAAAAATTTATTTAAATAAAATACTTTGAAAATGAAAAGTCTTGATGTAGTCAGATGGTTACTCTCTTAACATTAGGTATTACCCCCACTCAGACATCACTCAGAAATGATCAATGCAGGGACTCTTTCTGTGACACAAATGTCCCAGCCCTCCCTGGTCACCGCCTTCGCCATGGTAGAGTCATAGGTCTGAGGATGAGGAATGTGGCTGTCTCACCCTTGCTTGCAAAACAGATGGCCTTGGAGACCAGACTCCCTCAAAGGTGCCAGCTACAGGAAAAATATACTGATGTTCCTTGGCAACACTTACAGAACTTTCCATCAATGAGGTCCATCAATGGCTTCTTAAAGGAAAAGGGGGGAAATAGCAAAAACCTAAGGAAGAATGGACCTTTGAGTTAAATCCAGTGTTTGTTGGGAAAGGAGGGATCAAAAACCTCTATAGTAGCCACTAGGGCAAAAACTGTGTGTATGTGTGTGTGTAAGTGTGTGTACACTGTTCAATATGGTTCAATATGGTACCAATAGCCACATGTGACTATTTAAATTCATTGCAATGAAATAAAATTAAAGGTATACTAGCTC SEQ ID NO.: 33 SEQ ID NO.: 80CTTTCACTGGCAAGAGACGGAGTCCTGGGTTTCAGTTCCAGTTGCCTGCGGTGGGCTGTGTGAGTTTGCCAAAGTCCCCTGCCCTCTMKTPWKVLLGLLGACTGGGTCTCGGTTCCCTCGCCTGTCCACGTGAGGTTGGAGGAGCTGAACGCCGACGTCATTTTTAGCTAAGAGGGAGCAGGGTCCCCAALVTIITVPVVLLGAGTCGCCGGCCCAGGGTCTGCGCATCCGAGGCCGCGCGCCCTTTCCCCTCCCCCACGGCTCCTCCGGGCCCCGCACTCTGCGCCCCNKGTDDATADSRKTGGCTGCCGCCCAGCGCCCTACACCGCCCTCAGGGGGCCCTCGCGGGCTCCCCCCGGCCGGGATGCCAGTGCCCCGCGCCACGCGCGCYTLTDYLKNTYRLKCTGCTCCCGCGCCGCCTGCCCTGCAGCCTGCCCGCGGCGCCTTTATACCCAGCGGGCTCGGCGCTCACTAATGTTTAACTCGGGGCCLYSLRWISDHEYLYGAAACTTGCCAGCGGCGAGTGACTCCACCGCCCGGAGCAGCGGTGCAGGACGCGCGTCTCCGCCGCCCGCGGTGACTTCTGCCTGCGKQENNILVFNAEYGCTCCTTCTCTGAACGCTCACTTCCGAGGAGACGCCGACGATGAAGACACCGTGGAAGGTTCTTCTGGGACTGCTGGGTGCTGCTGCGNSSVFLENSTFDEFCTTGTCACCATCATCACCGTGCCCGTGGTTCTGCTGAACAAAGGCACAGATGATGCTACAGCTGACAGTCGCAAAACTTACACTCTAGHSINDYSISPDGQACTGATTACTTAAAAAATACTTATAGACTGAAGTTATACTCCTTAAGATGGATTTCAGATCATGAATATCTCTACAAACAAGAAAATFILLEYNYVKQWRHAATATCTTGGTATTCAATGCTGAATATGGAAACAGCTCAGTTTTCTTGGAGAACAGTACATTTGATGAGTTTGGACATTCTATCAATSYTASYDIYDLNKRGATTATTCAATATCTCCTGATGGGCAGTTTATTCTCTTAGAATACAACTACGTGAAGCAATGGAGGCATTCCTACACAGCTTCATATQLITEERIPNNTQWGACATTTATGATTTAAATAAAAGGCAGCTGATTACAGAAGAGAGGATTCCAAACAACACACAGTGGGTCACATGGTCACCAGTGGGTVTWSPVGHKLAYVWCATAAATTGGCATATGTTTGGAACAATGACATTTATGTTAAAATTGAACCAAATTTACCAAGTTACAGAATCACATGGACGGGGAAANNDIYVKIEPNLPSGAAGATATAATATATAATGGAATAACTGACTGGGTTTATGAAGAGGAAGTCTTCAGTGCCTACTCTGCTCTGTGGTGGTCTCCAAACYRITWTGKEDIIYNGGCACTTTTTTAGCATATGCCCAATTTAACGACACAGAAGTCCCACTTATTGAATACTCCTTCTACTCTGATGAGTCACTGCAGTACGITDWVYEEEVFSACCAAAGACTGTACGGGTTCCATATCCAAAGGCAGGAGCTGTGAATCCAACTGTAAAGTTCTTTGTTGTAAATACAGACTCTCTCAGCYSALWWSPNGTFLATCAGTCACCAATGCAACTTCCATACAAATCACTGCTCCTGCTTCTATGTTGATAGGGGATCACTACTTGTGTGATGTGACATGGGCAYAQFNDTEVPLIEYACACAAGAAAGAATTTCTTTGCAGTGGCTCAGGAGGATTCAGAACTATTCGGTCATGGATATTTGTGACTATGATGAATCCAGTGGASFYSDESLQYPKTVAGATGGAACTGCTTAGTGGCACGGCAACACATTGAAATGAGTACTACTGGCTGGGTTGGAAGATTTAGGCCTTCAGAACCTCATTTTRVPYPKAGAVNPTVACCCTTGATGGTAATAGCTTCTACAAGATCATCAGCAATGAAGAAGGTTACAGACACATTTGCTATTTCCAAATAGATAAAAAAGACKFFVVNTDSLSSVTTGCACATTTATTACAAAAGGCACCTGGGAAGTCATCGGGATAGAAGCTCTAACCAGTGATTATCTATACTACATTAGTAATGAATATNATSIQITAPASMLAAAGGAATGCCAGGAGGAAGGAATCTTTATAAAATCCAACTTAGTGACTATACAAAAGTGACATGCCTCAGTTGTGAGCTGAATCCGIGDHYLCDVTWATQGAAAGGTGTCAGTACTATTCTGTGTCATTCAGTAAAGAGGCGAAGTATTATCAGCTGAGATGTTCCGGTCCTGGTCTGCCCCTCTATERISLQWLRRIQNYACTCTACACAGCAGCGTGAATGATAAAGGGCTGAGAGTCCTGGAAGACAATTCAGCTTTGGATAAAATGCTGCAGAATGTCCAGATGSVMDICDYDESSGRCCCTCCAAAAAACTGGACTTCATTATTTTGAATGAAACAAAATTTTGGTATCAGATGATCTTGCCTCCTCATTTTGATAAATCCAAGWNCLVARQHIEMSTAAATATCCTCTACTATTAGATGTGTATGCAGGCCCATGTAGTCAAAAAGCAGACACTGTCTTCAGACTGAACTGGGCCACTTACCTTTGWVGRFRPSEPHFGCAAGCACAGAAAACATTATAGTAGCTAGCTTTGATGGCAGAGGAAGTGGTTACCAAGGAGATAAGATCATGCATGCAATCAACAGATLDGNSFYKIISNEAGACTGGGAACATTTGAAGTTGAAGATCAAATTGAAGCAGCCAGACAATTTTCAAAAATGGGATTTGTGGACAACAAACGAATTGCAEGYRHICYFQIDKKATTTGGGGCTGGTCATATGGAGGGTACGTAACCTCAATGGTCCTGGGATCGGGAAGTGGCGTGTTCAAGTGTGGAATAGCCGTGGCGDCTFITKGTWEVIGCCTGTATCCCGGTGGGAGTACTATGACTCAGTGTACACAGAACGTTACATGGGTCTCCCAACTCCAGAAGACAACCTTGACCATTACIEALTSDYLYYISNAGAAATTCAACAGTCATGAGCAGAGCTGAAAATTTTAAACAAGTTGAGTACCTCCTTATTCATGGAACAGCAGATGATAACGTTCACEYKGMPGGRNLYKITTTCAGCAGTCAGCTCAGATCTCCAAAGCCCTGGTCGATGTTGGAGTGGATTTCCAGGCAATGTGGTATACTGATGAAGACCATGGAQLSDYTKVTCLSCEATAGCTAGCAGCACAGCACACCAACATATATATACCCACATGAGCCACTTCATAAAACAATGTTTCTCTTTACCTTAGCACCTCAAALNPERCQYYSVSFSATACCATGCCATTTAAAGCTTATTAAAACTCATTTTTGTTTTCATTATCTCAAAACTGCACTGTCAAGATGATGATGATCTTTAAAAKEAKYYQLRCSGPGTACACACTCAAATCAAGAAACTTAAGGTTACCTTTGTTCCCAAATTTCATACCTATCATCTTAAGTAGGGACTTCTGTCTTCACAACLPLYTLHSSVNDKGAGATTATTACCTTACAGAAGTTTGAATTATCCGGTCGGGTTTTATTGTTTAAAATCATTTCTGCATCAGCTGCTGAAACAACAAATALRVLEDNSALDKMLGGAATTGTTTTTATGGAGGCTTTGCATAGATTCCCTGAGCAGGATTTTAATCTTTTTCTAACTGGACTGGTTCAAATGTTGTTCTCTQNVQMPSKKLDFIITCTTTAAAGGGATGGCAAGATGTGGGCAGTGATGTCACTAGGGCAGGGACAGGATAAGAGGGATTAGGGAGAGAAGATAGCAGGGCALNETKFWYQMILPPTGGCTGGGAACCCAAGTCCAAGCATACCAACACGAGCAGGCTACTGTCAGCTCCCCTCGGAGAAGAGCTGTTCACAGCCAGACTGGCHFDKSKKYPLLLDVACAGTTTTCTGAGAAAGACTATTCAAACAGTCTCAGGAAATCAAATATGCAAAGCACTGACTTCTAAGTAAAACCACAGCAGTTGAAYAGPCSQKADTVFRAAGACTCCAAAGAAATGTAAGGGAAACTGCCAGCAACGCAGGCCCCCAGGTGCCAGTTATGGCTATAGGTGCTACAAAAACACAGCALNWATYLASTENIIAGGGTGATGGGAAAGCATTGTAAATGTGCTTTTAAAAAAAAATACTGATGTTCCTAGTGAAAGAGGCAGCTTGAAACTGAGATGTGAVASFDGRGSGYQGDACACATCAGCTTGCCCTGTTAAAAGATGAAAATATTTGTATCACAAATCTTAACTTGAAGGAGTCCTTGCATCAATTTTTCTTATTTKIMHAINRRLGTFECATTTCTTTGAGTGTCTTAATTAAAAGAATATTTTAACTTCCTTGGACTCATTTTAAAAAATGGAACATAAAATACAATGTTATGTAVEDQIEAARQFSKMTTATTATTCCCATTCTACATACTATGGAATTTCTCCCAGTCATTTAATAAATGTGCCTTCATTTTTTCAGAAAAAAAAAAAAAAAGFVDNKRIAIWGWS YGGYVTSMVLGSGS GVFKCGIAVAPVSR WEYYDSVYTERYMGLPTPEDNLDHYRNS TVMSRAENFKQVEY LLIHGTADDNVHFQ QSAQISKALVDVGVDFQAMWYTDEDHGI ASSTAHQHIYTHMS HFIKQCFSLP SEQ ID NO.: 34 SEQ ID NO.: 81CGCAGCGGGTCCTCTCTATCTAGCTCCAGCCTCTCGCCTGCGCCCCACTCCCCGCGTCCCGCGTCCTAGCCGACCATGGCCGGGCCCMAGPLRAPLLLLAICTGCGCGCCCCGCTGCTCCTGCTGGCCATCCTGGCCGTGGCCCTGGCCGTGAGCCCCGCGGCCGGCTCCAGTCCCGGCAAGCCGCCGLAVALAVSPAAGSSCGCCTGGTGGGAGGCCCCATGGACGCCAGCGTGGAGGAGGAGGGTGTGCGGCGTGCACTGGACTTTGCCGTCGGCGAGTACAACAAAPGKPPRLVGGPMDAGCCAGCAACGACATGTACCACAGCCGCGCGCTGCAGGTGGTGCGCGCCCGCAAGCAGATCGTAGCTGGGGTGAACTACTTCTTGGACSVEEEGVRRALDFAGTGGAGCTGGGCCGAACCACGTGTACCAAGACCCAGCCCAACTTGGACAACTGCCCCTTCCATGACCAGCCACATCTGAAAAGGAAAVGEYNKASNDMYHSGCATTCTGCTCTTTCCAGATCTACGCTGTGCCTTGGCAGGGCACAATGACCTTGTCGAAATCCACCTGTCAGGACGCCTAGGGGTCTRALQVVRARKQIVAGTACCGGGCTGGCCTGTGCCTATCACCTCTTATGCACACCTCCCACCCCCTGTATTCCCACCCCTGGACTGGTGGCCCCTGCCTTGGLGVNYFLDVELGRTGGAAGGTCTCCCCATGTGCCTGCACCAGGAGACAGACAGAGAAGGCAGCAGGCGGCCTTTGTTGCTCAGCAAGGGGCTCTGCCCTCCTCTKTQPNLDNCPFCTCCTTCCTTCTTGCTTCTCATAGCCCCGGTGTGCGGTGCATACACCCCCACCTCCTGCAATAAAATAGTAGCATCGGCAAAAAAAAHDQPHLKRKAFCSF AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA QIYAVPWQGTMTSK STCQDASEQ ID NO.: 35 SEQ ID NO.: 82CCCAGCGGCCCTGCAGACTTGGCACAGAGCACACCCACCTGCCTTTGTCACAGCACACTAAGAAGGTTCTCTGTGGTGACCAGGCTGMEGSLQLLACLACVGGTAGAGGGCTGCTGGGTCTGCAGGCGTCAGAGCATGGAGGGGTCCCTCCAACTCCTGGCCTGCTTGGCCTGTGTGCTCCAGATGGGLQMGSLVKTRRDASATCCCTTGTGAAAACTAGAAGAGACGCTTCGGGGGATCTGCTCAACACAGAGGCGCACAGTGCCCCGGCGCAGCGCTGGTCCATGCAGDLLNTEAHSAPAQGGTGCCCGCGGAGGTGAACGCGGAGGCTGGCGACGCGGCGGTGCTGCCCTGCACCTTCACGCACCCGCACCGCCACTACGACGGGCCRWSMQVPAEVNAEAGCTGACGGCCATCTGGCGCTCGGGCGAGCCGTACGCGGGCCCGCAGGTGTTCCGCTGCACCGCGGCGCCGGGCAGCGAGCTGTGCCAGDAAVLPCTFTHPHGACGGCGCTGAGCCTGCACGGCCGCTTCCGCCTGCTGGGCAACCCGCGCCGCAACGACCTGTCCCTGCGCGTCGAGCGCCTCGCCCTRHYDGPLTAIWRSGGGCGGACAGCGGCCGCTACTTCTGCCGCGTGGAGTTCACCGGCGACGCCCACGATCGCTATGAGAGTCGCCATGGGGTCCGTCTGCGEPYAGPQVFRCTAACGTGACTGCTGCGCCGCGGATCGTCAACATCTCGGTGCTGCCGGGCCCCGCGCACGCCTTCCGCGCGCTCTGCACCGCCGAGGGGGAPGSELCQTALSLHGGCCCCCGCCCGCCCTCGCCTGGTCGGGTCCCGCCCCAGGCAACAGCTCCGCTGCCCTGCAGGGCCAGGGTCACGGCTACCAGGTGACRFRLLGNPRRNDLSCGCCGAGTTGCCCGCGCTGACCCGCGACGGCCGCTACACGTGCACGGCGGCCAATAGCCTGGGCCGCGCCGAGGCCAGCGTCTACCTLRVERLALADSGRYGTTCCGCTTCCACGGCGCCCCCGGAACCTCGACCCTAGCGCTCCTGCTGGGCGCGCTGGGCCTCAAGGCCTTGCTGCTGCTTGGCATFCRVEFTGDAHDRYTCTGGGAGCGCGTGCCACCCGACGCCGACTAGATCACCTGGTCCCCCAGGACACCCCTCCACGTGCGGACCAGGACACTTCACCTATESRHGVRLRVTAAPCTGGGGCTCAGCTGAAGAAATAGAAGATCTGAAAGACCTGCATAAACTCCAACGCTAGRIVNISVLPGPAHA FRALCTAEGEPPPA LAWSGPAPGNSSAA LQGQGHGYQVTAELPALTRDGRYTCTAA NSLGRAEASVYLFR FHGAPGTSTLALLL GALGLKALLLLGILGARATRRRLDHLVP QDTPPRADQDTSPI WGSAEEIEDLKDLH KLQR SEQ ID NO.: 36TTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAATTCTAATACGACTCACTATAGGGAGACGAGAGCACCTGGATAGGTTCGCGTGGCGCGCCGCATGCGTCGACGGATCCTGAGAACTTCAGGCTCCTGGGCAACGTGCTGGTTATTGTGCTGTCTCATCATTTTGGCAAAGAATTCACTCCTCAGGTGCAGGCTGCCTATCAGAAGGTGGTGGCTGGTGTGGCCAATGCCCTGGCTCACAAATACCACTGAGATCTTTTTCCCTCTGCCAAAAATTATGGGGACATCATGAAGCCCCTTGAGCATCTGACTTCTGGCTAATAAAGGAAATTTATTTTCATTGCAAAAAAAAAAAGCGGCCGCTAACTGTTGGTGCAGGCGCTCGGACCGCTAGCTTGGCGTAATCATGGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCAATGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGGACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTGACGTCTAAGAAACCATTATTATCATGACATTAACCTATAAAAATAGGCGTATCACGAGGCCCTTTCGTCTCGCGCGTTTCGGTGATGACGGTGAAAACCTCTGACACATGCAGCTCCCGGAGACGGTCACAGCTTGTCTGTAAGCGGATGCCGGGAGCAGACAAGCCCGTCAGGGCGCGTCAGCGGGTGTTGGCGGGTGTCGGGGCTGGCTTAACTATGCGGCATCAGAGCAGATTGTACTGAGAGTGCACCATATGCGGTGTGAAATACCGCACAGATGCGTAAGGAGAAAATACCGCATCAGGCGCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGG SEQ ID NO.: 37TTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAATTCGAGCTCACATACGATTTAGGTGACACTATAGGCCTGCACCAACAGTTAACACGGCGCGCCGCATGCGTCGACGGATCCTGAGAACTTCAGGCTCCTGGGCAACGTGCTGGTTATTGTGCTGTCTCATCATTTTGGCAAAGAATTCACTCCTCAGGTGCAGGCTGCCTATCAGAAGGTGGTGGCTGGTGTGGCCAATGCCCTGGCTCACAAATACCACTGAGATCTTTTTCCCTCTGCCAAAAATTATGGGGACATCATGAAGCCCCTTGAGCATCTGACTTCTGGCTAATAAAGGAAATTTATTTTCATTGCAAAAAAAAAAAGCGGCCGCTAGAGTCGGCCGCAGCGGCCGAGCTTGGCGTAATCATGGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCAAAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTGACGTCTAAGAAACCATTATTATCATGACATTAACCTATAAAAATAGGCGTATCACGAGGCCCTTTCGTCTCGCGCGTTTCGGTGATGACGGTGAAAACCTCTGACACATGCAGCTCCCGGAGACGGTCACAGCTTGTCTGTAAGCGGATGCCGGGAGCAGACAAGCCCGTCAGGGCGCGTCAGCGGGTGTTGGCGGGTGTCGGGGCTGGCTTAACTATGCGGCATCAGAGCAGATTGTACTGAGAGTGCACCATATGCGGTGTGAAATACCGCACAGATGCGTAAGGAGAAAATACCGCATCAGGCGCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGG SEQ ID NO.: 38TTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAATTCTAATACGACTCACTATAGGGAGATGGAGAAAAAAATCACTGGACGCGTGGCGCGCCATTAATTAATGCGGCCGCTAGCTCGAGTGATAATAAGCGGATGAATGGCTGCAGGCATGCAAGCTTGGCGTAATCATGGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCAATGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGGACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTGACGTCTAAGAAACCATTATTATCATGACATTAACCTATAAAAATAGGCGTATCACGAGGCCCTTTCGTCTCGCGCGTTTCGGTGATGACGGTGAAAACCTCTGACACATGCAGCTCCCGGAGACGGTCACAGCTTGTCTGTAAGCGGATGCCGGGAGCAGACAAGCCCGTCAGGGCGCGTCAGCGGGTGTTGGCGGGTGTCGGGGCTGGCTTAACTATGCGGCATCAGAGCAGATTGTACTGAGAGTGCACCATATGCGGTGTGAAATACCGCACAGATGCGTAAGGAGAAAATACCGCATCAGGCGCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGG SEQ ID NO.:39TTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAATTCAATTAACCCTCACTAAAGGGAGACTTGTTCCAAATGTGTTAGGcgCGCCGCATGCGTCGACGGATCCTGAGAACTTCAGGCTCCTGGGCAACGTGCTGGTTATTGTGCTGTCTCATCATTTTGGCAAAGAATTCACTCCTCAGGTGCAGGCTGCCTATCAGAAGGTGGTGGCTGGTGTGGCCAATGCCCTGGCTCACAAATACCACTGAGATCTTTTTCCCTCTGCCAAAAATTATGGGGACATCATGAAGCCCCTTGAGCATCTGACTTCTGGCTAATAAAGGAAATTTATTTTCATTGCAAAAAAAAAAAGCGGCCGCTCTTCTATAGTGTCACCTAAATGGCCCAGCGGCCGAGCTTGGCGTAATCATGGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCAAAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTGACGTCTAAGAAACCATTATTATCATGACATTAACCTATAAAAATAGGCGTATCACGAGGCCCTTTCGTCTCGCGCGTTTCGGTGATGACGGTGAAAACCTCTGACACATGCAGCTCCCGGAGACGGTCACAGCTTGTCTGTAAGCGGATGCCGGGAGCAGACAAGCCCGTCAGGGCGCGTCAGCGGGTGTTGGCGGGTGTCGGGGCTGGCTTAACTATGCGGCATCAGAGCAGATTGTACTGAGAGTGCACCATATGCGGTGTGAAATACCGCACAGATGCGTAAGGAGAAAATACCGCATCAGGCGCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGG SEQ ID NO.: 40AATTCTAATACGACTCACTATAGGGAGACGAGAGCACCTGGATAGGTT SEQ ID NO.: 41GCCTGCACCAACAGTTAACA SEQ ID NO.: 42 CAGGCCCAGGAGTCCAATT SEQ ID NO.: 43TCCCGTCTTTGGGTCAAAA SEQ ID NO.: 44 GCGCCGCGGATCGTCAACA SEQ ID NO.: 45ACACGTGCACGGCGGCCAA SEQ ID NO.: 46TCGCGCGTTTCGGTGATGACGGTGAAAACCTCTGACACATGCAGCTCCCGGAGACGGTCACAGCTTGTCTGTAAGCGGATGCCGGGAGCAGACAAGCCCGTCAGGGCGCGTCAGCGGGTGTTGGCGGGTGTCGGGGCTGGCTTAACTATGCGGCATCAGAGCAGATTGTACTGAGAGTGCACCATATGCGGTGTGAAATACCGCACAGATGCGTAAGGAGAAAATACCGCATCAGGCGCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGCCAAGCTTTTCCAAAAAACTACCGTTGTTATAGGTGTCTCTTGAACACCTATAACAACGGTAGTGGATCCCGCGTCCTTTCCACAAGATATATAAACCCAAGAAATCGAAATACTTTCAAGTTACGGTAAGCATATGATAGTCCATTTTAAAACATAATTTTAAAACTGCAAACTACCCAAGAAATTATTACTTTCTACGTCACGTATTTTGTACTAATATCTTTGTGTTTACAGTCAAATTAATTCTAATTATCTCTCTAACAGCCTTGTATCGTATATGCAAATATGAAGGAATCATGGGAAATAGGCCCTCTTCCTGCCCGACCTTGGCGCGCGCTCGGCGCGCGGTCACGCTCCGTCACGTGGTGCGTTTTGCCTGCGCGTCTTTCCACTGGGGAATTCATGCTTCTCCTCCCTTTAGTGAGGGTAATTCTCTCTCTCTCCCTATAGTGAGTCGTATTAATTCCTTCTCTTCTATAGTGTCACCTAAATCGTTGCAATTCGTAATCATGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAAAAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTATTGGTGTGGAAAGTCCCCAGGCTCCCCAGCAGGCAGAAGTATGCAAAGCATGCATCTCAATTAGTCAGCAACCAGGTGTGGAAAGTCCCCAGGCTCCCCAGCAGGCAGAAGTATGCAAAGCATGCATCTCAATTAGTCAGCAACCATAGTCCCGCCCCTAACTCCGCCCATCCCGCCCCTAACTCCGCCCAGTTCCGCCCATTCTCCGCCCCATGGCTGACTAATTTTTTTTATTTATGCAGAGGCCGAGGCCGCCTCGGCCTCTGAGCTATTCCAGAAGTAGTGAGGAGGCTTTTTTGGAGGCCTAGGCTTTTGCAAAAAGCTAGCTTGCATGCCTGCAGGTCGGCCGCCACGACCGGTGCCGCCACCATCCCCTGACCCACGCCCCTGACCCCTCACAAGGAGACGACCTTCCATGACCGAGTACAAGCCCACGGTGCGCCTCGCCACCCGCGACGACGTCCCCCGGGCCGTACGCACCCTCGCCGCCGCGTTCGCCGACTACCCCGCCACGCGCCACACCGTCGACCCGGACCGCCACATCGAGCGGGTCACCGAGCTGCAAGAACTCTTCCTCACGCGCGTCGGGCTCGACATCGGCAAGGTGTGGGTCGCGGACGACGGCGCCGCGGTGGCGGTCTGGACCACGCCGGAGAGCGTCGAAGCGGGGGCGGTGTTCGCCGAGATCGGCCCGCGCATGGCCGAGTTGAGCGGTTCCCGGCTGGCCGCGCAGCAACAGATGGAAGGCCTCCTGGCGCCGCACCGGCCCAAGGAGCCCGCGTGGTTCCTGGCCACCGTCGGCGTCTCGCCCGACCACCAGGGCAAGGGTCTGGGCAGCGCCGTCGTGCTCCCCGGAGTGGAGGCGGCCGAGCGCGCCGGGGTGCCCGCCTTCCTGGAGACCTCCGCGCCCCGCAACCTCCCCTTCTACGAGCGGCTCGGCTTCACCGTCACCGCCGACGTCGAGGTGCCCGAAGGACCGCGCACCTGGTGCATGACCCGCAAGCCCGGTGCCTGACGCCCGCCCCACGACCCGCAGCGCCCGACCGAAAGGAGCGCACGACCCCATGGCTCCGACCGAAGCCACCCGGGGCGGCCCCGCCGACCCCGCACCCGCCCCCGAGGCCCACCGACTCTAGAGGATCATAATCAGCCATACCACATTTGTAGAGGTTTTACTTGCTTTAAAAAACCTCCCACACCTCCCCCTGAACCTGAAACATAAAATGAATGCAATTGTTGTTGTTAACTTGTTTATTGCAGCTTATAATGGTTACAAATAAAGCAATAGCATCACAAATTTCACAAATAAAGCATTTTTTTCACTGCAATCTAAGAAACCATTATTATCATGACATTAACCTATAAAAATAGGCGTATCACGAGGCCCTTTCGTC SEQ ID NO.: 47TAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAACCGTCAGATCCGCTAGCGCTACCGGACTCAGATCTCGAGCTCAAGCTTCGAATTCTGCAGTCGACGGTACCGCGGGCCCGGGATCCACCGGGGCCGCGACTCTAGATCATAATCAGCCATACCACATTTGTAGAGGTTTTACTTGCTTTAAAAAACCTCCCACACCTCCCCCTGAACCTGAAACATAAAATGAATGCAATTGTTGTTGTTAACTTGTTTATTGCAGCTTATAATGGTTACAAATAAAGCAATAGCATCACAAATTTCACAAATAAAGCATTTTTTTCACTGCATTCTAGTTGTGGTTTGTCCAAACTCATCAATGTATCTTAAGGCGTAAATTGTAAGCGTTAATATTTTGTTAAAATTCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGCCGAAATCGGCAAAATCCCTTATAAATCAAAAGAATAGACCGAGATAGGGTTGAGTGTTGTTCCAGTTTGGAACAAGAGTCCACTATTAAAGAACGTGGACTCCAACGTCAAAGGGCGAAAAACCGTCTATCAGGGCGATGGCCCACTACGTGAACCATCACCCTAATCAAGTTTTTTGGGGTCGAGGTGCCGTAAAGCACTAAATCGGAACCCTAAAGGGAGCCCCCGATTTAGAGCTTGACGGGGAAAGCCGGCGAACGTGGCGAGAAAGGAAGGGAAGAAAGCGAAAGGAGCGGGCGCTAGGGCGCTGGCAAGTGTAGCGGTCACGCTGCGCGTAACCACCACACCCGCCGCGCTTAATGCGCCGCTACAGGGCGCGTCAGGTGGCACTTTTCGGGGAAATGTGCGCGGAACCCCTATTTGTTTATTTTTCTAAATACATTCAAATATGTATCCGCTCATGAGACAATAACCCTGATAAATGCTTCAATAATATTGAAAAAGGAAGAGTCCTGAGGCGGAAAGAACCAGCTGTGGAATGTGTGTCAGTTAGGGTGTGGAAAGTCCCCAGGCTCCCCAGCAGGCAGAAGTATGCAAAGCATGCATCTCAATTAGTCAGCAACCAGGTGTGGAAAGTCCCCAGGCTCCCCAGCAGGCAGAAGTATGCAAAGCATGCATCTCAATTAGTCAGCAACCATAGTCCCGCCCCTAACTCCGCCCATCCCGCCCCTAACTCCGCCCAGTTCCGCCCATTCTCCGCCCCATGGCTGACTAATTTTTTTTATTTATGCAGAGGCCGAGGCCGCCTCGGCCTCTGAGCTATTCCAGAAGTAGTGAGGAGGCTTTTTTGGAGGCCTAGGCTTTTGCAAAGATCGATCAAGAGACAGGATGAGGATCGTTTCGCATGATTGAACAAGATGGATTGCACGCAGGTTCTCCGGCCGCTTGGGTGGAGAGGCTATTCGGCTATGACTGGGCACAACAGACAATCGGCTGCTCTGATGCCGCCGTGTTCCGGCTGTCAGCGCAGGGGCGCCCGGTTCTTTTTGTCAAGACCGACCTGTCCGGTGCCCTGAATGAACTGCAAGACGAGGCAGCGCGGCTATCGTGGCTGGCCACGACGGGCGTTCCTTGCGCAGCTGTGCTCGACGTTGTCACTGAAGCGGGAAGGGACTGGCTGCTATTGGGCGAAGTGCCGGGGCAGGATCTCCTGTCATCTCACCTTGCTCCTGCCGAGAAAGTATCCATCATGGCTGATGCAATGCGGCGGCTGCATACGCTTGATCCGGCTACCTGCCCATTCGACCACCAAGCGAAACATCGCATCGAGCGAGCACGTACTCGGATGGAAGCCGGTCTTGTCGATCAGGATGATCTGGACGAAGAGCATCAGGGGCTCGCGCCAGCCGAACTGTTCGCCAGGCTCAAGGCGAGCATGCCCGACGGCGAGGATCTCGTCGTGACCCATGGCGATGCCTGCTTGCCGAATATCATGGTGGAAAATGGCCGCTTTTCTGGATTCATCGACTGTGGCCGGCTGGGTGTGGCGGACCGCTATCAGGACATAGCGTTGGCTACCCGTGATATTGCTGAAGAGCTTGGCGGCGAATGGGCTGACCGCTTCCTCGTGCTTTACGGTATCGCCGCTCCCGATTCGCAGCGCATCGCCTTCTATCGCCTTCTTGACGAGTTCTTCTGAGCGGGACTCTGGGGTTCGAAATGACCGACCAAGCGACGCCCAACCTGCCATCACGAGATTTCGATTCCACCGCCGCCTTCTATGAAAGGTTGGGCTTCGGAATCGTTTTCCGGGACGCCGGCTGGATGATCCTCCAGCGCGGGGATCTCATGCTGGAGTTCTTCGCCCACCCTAGGGGGAGGCTAACTGAAACACGGAAGGAGACAATACCGGAAGGAACCCGCGCTATGACGGCAATAAAAAGACAGAATAAAACGCACGGTGTTGGGTCGTTTGTTCATAAACGCGGGGTTCGGTCCCAGGGCTGGCACTCTGTCGATACCCCACCGAGACCCCATTGGGGCCAATACGCCCGCGTTTCTTCCTTTTCCCCACCCCACCCCCCAAGTTCGGGTGAAGGCCCAGGGCTCGCAGCCAACGTCGGGGCGGCAGGCCCTGCCATAGCCTCAGGTTACTCATATATACTTTAGATTGATTTAAAACTTCATTTTTAATTTAAAAGGATCTAGGTGAAGATCCTTTTTGATAATCTCATGACCAAAATCCCTTAACGTGAGTTTTCGTTCCACTGAGCGTCAGACCCCGTAGAAAAGATCAAAGGATCTTCTTGAGATCCTTTTTTTCTGCGCGTAATCTGCTGCTTGCAAACAAAAAAACCACCGCTACCAGCGGTGGTTTGTTTGCCGGATCAAGAGCTACCAACTCTTTTTCCGAAGGTAACTGGCTTCAGCAGAGCGCAGATACCAAATACTGTCCTTCTAGTGTAGCCGTAGTTAGGCCACCACTTCAAGAACTCTGTAGCACCGCCTACATACCTCGCTCTGCTAATCCTGTTACCAGTGGCTGCTGCCAGTGGCGATAAGTCGTGTCTTACCGGGTTGGACTCAAGACGATAGTTACCGGATAAGGCGCAGCGGTCGGGCTGAACGGGGGGTTCGTGCACACAGCCCAGCTTGGAGCGAACGACCTACACCGAACTGAGATACCTACAGCGTGAGCTATGAGAAAGCGCCACGCTTCCCGAAGGGAGAAAGGCGGACAGGTATCCGGTAAGCGGCAGGGTCGGAACAGGAGAGCGCACGAGGGAGCTTCCAGGGGGAAACGCCTGGTATCTTTATAGTCCTGTCGGGTTTCGCCACCTCTGACTTGAGCGTCGATTTTTGTGATGCTCGTCAGGGGGGCGGAGCCTATGGAAAAACGCCAGCAACGCGGCCTTTTTACGGTTCCTGGCCTTTTGCTGGCCTTTTGCTCACATGTTCTTTCCTGCGTTATCCCCTGATTCTGTGGATAACCGTATTACCGCCATGCATSEQ ID NO.: 83 Identical toATGGAAAAGTCCATCTGGCTGCTGGCCTGCTTGGCGTGGGTTCTCCCGACAGGCTCATTTGTGAGAACTAAAATAGATACTACGGAGSEQ ID NO.: 48AACTTGCTCAACACAGAGGTGCACAGCTCGCCAGCGCAGCGCTGGTCCATGCAGGTGCCACCCGAGGTGAGCGCGGAGGCAGGCGACMEKSIWLLACLAWGCGGCAGTGCTGCCCTGCACCTTCACGCACCCGCACCGCCACTACGACGGGCCGCTGACGGCCATCTGGCGCGCGGGCGAGCCCTATVLPTGSFVRTKIDGCGGGCCCGCAGGTGTTCCGCTGCGCTGCGGCGCGGGGCAGCGAGCTCTGCCAGACGGCGCTGAGCCTGCACGGCCGCTTCCGGCTGTTENLLNTEVHSSCTGGGCAACCCGCGCCGCAACGACCTCTCGCTGCGCGTCGAGCGCCTCGCCCTGGCTGACGACCGCCGCTACTTCTGCCGCGTCGAGPAQRWSMQVPPEVTTCGCCGGCGACGTCCATGACCGCTACGAGAGCCGCCACGGCGTCCGGCTGCACGTGACAGCCGCGCCGCGGATCGTCAACATCTCGSAEAGDAAVLPCTGTGCTGCCCAGTCCGGCTCACGCCTTCCGCGCGCTCTGCACTGCCGAAGGGGAGCCGCCGCCCGCCCTCGCCTGGTCCGGCCCGGCCFTHPHRHYDGPLTCTGGGCAACAGCTTGGCAGCCGTGCGGAGCCCGCGTGAGGGTCACGGCCACCTAGTGACCGCCGAACTGCCCGCACTGACCCATGACAIWRAGEPYAGPQGGCCGCTACACGTGTACGGCCGCCAACAGCCTGGGCCGCTCCGAGGCCAGCGTCTACCTGTTCCGCTTCCATGGCGCCAGCGGGGCCVFRCAAARGSELCTCGACGGTCGCCCTCCTGCTCGGCGCTCTCGGCTTCAAGGCGCTGCTGCTGCTCGGGGTCCTGGCCGCCCGCGCTGCCCGCCGCCGCQTALSLHGRFRLLCCAGAGCATCTGGACACCCCGGACACCCCACCACGGTCCCAGGCCCAGGAGTCCAATTATGAAAATTTGAGCCAGATGAACCCCCGGGNPRRNDLSLRVE AGCCCACCAGCCACCATGTGCTCACCGTGA RLALADDRRYFCR VEFAGDVHDRYESRHGVRLHVTAAPR IVNISVLPSPAHA FRALCTAEGEPPP ALAWSGPALGNSL AAVRSPREGHGHLVTAELPALTHDGR YTCTAANSLGRSE ASVYLFRFHGASG ASTVALLLGALGF KALLLLGVLAARAARRRPEHLDTPDT PPRSQAQESNYEN LSQMNPRSPPATM CSP SEQ ID NO.: 84 IdenticaltoATGCCGGCGCTGCTGCCTGTGGCCTCCCGCCTTTTGTTGCTACCCCGAGTCTTGCTGACCATGGCCTCTGGAAGCCCTCCGACCCAGSEQ ID NO.: 49CCCTCGCCGGCCTCGGATTCCGGCTCTGGCTACGTTCCGGGCTCGGTCTCTGCAGCCTTTGTTACTTGCCCCAACGAGAAGGTCGCCMIGSGLAGSGGAGGAAGGAGATCGCCAGGGCCGTGGTGGAGAAGCGCCTAGCAGCCTGCGTCAACCTCATCCCTCAGATTACATCCATCTATGAGTGGAAAPSSTVTWCALFSNHGGGAAGATCGAGGAAGACAGTGAGGTGCTGATGATGATTAAAACCCAAAGTTCCTTGGTCCCAGCTTTGACAGATTTTGTTCGTTCTVAATQASLLLSFVWGTGCACCCTTACGAAGTGGCCGAGGTAATTGCATTGCCTGTGGAACAGGGGAACTTTCCGTACCTGCAGTGGGTGCGCCAGGTCACAMPALLPVASRLLLL GAGTCAGTTTCTGACTCTATCACAGTCCTGCCATGA PRVLLTMASGSPPTQPSPASDSGSGYVP GSVSAAFVTCPNEK VAKEIARAVVEKRL AACVNLIPQITSIYEWKGKIEEDSEVLM MIKTQSSLVPALTD FVRSVHPYEVAEVI ALPVEQGNFPYLQWVRQVTESVSDSITV LP SEQ ID NO. 85:CATGTGCCAACATGCAGGTTTGCTCATATNTATACTTTTGCCATGTTGGTGTGCTGCACCCATTAACTCGTCATTTAGCATTAGGTATATTTCTTAATGCTATCCCTCCCCCCTCCCTCCACCCCACAACAGTCCCCGCTGGTGTGTGATGTTCCCAAATTTTTTTTTTCTCATCANCATTATCNCTAAACAACATTGAATGAAACAACATTGAGGATCTGCTATATTTGAAAATAAAAATATAACTAAAAATAATACAAATTTTAAAAATACAGTGTAACAACTATTTACATAGAATTTACATTGTATTAGGTATTGNANGTAATCTAGAGTTGATTTAAAGGAGGGGNGTCCAAACTTTTGGCTTCCCTGGGCCACACTGGAANAANAATTGTCTTGGGCTACCCATAAAATACACTAACAATAGCTGATAACGA SEQ ID NO. 86GCTGATTTACAGAGTTTCCTCCTTATAATATTCAAATGTCCATTTTCAATAACAGCAACAAACTACAAAGAAACAGGAAAGTATGGTCTACTCACAGAReferencesPatents

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We claim:
 1. An antibody or antigen binding fragment capable of specificbinding to a polypeptide consisting of SEQ ID NO.:48 or to a polypeptideconsisting of SEQ ID NO.:82, wherein the antibody or antigen bindingfragment is linked to a toxin or a cytokine.
 2. The antibody or antigenbinding fragment of claim 1, wherein said antibody has sub-nanomolaraffinity for the polypeptide.
 3. The antibody or antigen bindingfragment of claim 1, wherein the antibody binds to the polypeptide ofSEQ ID NO.:48 with greater affinity than to the polypeptide of SEQ IDNO.:82.
 4. The antibody or antigen binding fragment of claim 1, whereinthe antibody is a polyclonal antibody, a monoclonal antibody, a chimericantibody, a humanized antibody or a human antibody.
 5. The antibody orantigen binding fragment of claim 1, wherein the antigen bindingfragment is a FV, a Fab, a Fab′ or a (Fab′)₂.
 6. The antibody or antigenbinding fragment of claim 1, wherein the antibody or antigen bindingfragment binds to a polypeptide consisting of SEQ ID NO.:48 and to apolypeptide consisting of SEQ ID NO.:82.
 7. A pharmaceutical compositioncomprising an antibody or antigen binding fragment capable of specificbinding to a polypeptide consisting of SEQ ID NO.:48 or to a polypeptideconsisting of SEQ ID NO.:82, wherein the antibody or antigen bindingfragment is linked to a toxin or a cytokine.
 8. The pharmaceuticalcomposition of claim 7, further comprising an antiresorptive drug or adrug increasing bone mineral density.
 9. The pharmaceutical compositionof claim 7, wherein the antibody or antigen binding fragment hassub-nanomolar affinity for the polypeptide.
 10. The pharmaceuticalcomposition of claim 7, wherein the antibody or antigen binding fragmentbinds to the polypeptide of SEQ ID NO.:48 with greater affinity than tothe polypeptide of SEQ ID NO.:82.
 11. The pharmaceutical composition ofclaim 7, wherein the antibody or antigen binding fragment is apolyclonal antibody, a monoclonal antibody, a chimeric antibody, ahumanized antibody or a human antibody.
 12. The pharmaceuticalcomposition of claim 7, wherein the antibody or antigen binding fragmentis a FV, a Fab, a Fab′ or a (Fab′)₂.
 13. The pharmaceutical compositionof claim 7, wherein the antibody or antigen binding fragment binds to apolypeptide consisting of SEQ ID NO.:48 and to a polypeptide consistingof SEQ ID NO.:82.